2024/06/22 更新

写真a

オオハザマ アツシ
大峡 淳
OHAZAMA Atsushi
所属
教育研究院 医歯学系 歯学系列 教授
医歯学総合研究科 口腔生命科学専攻 摂食環境制御学 教授
職名
教授
外部リンク

学位

  • 博士(歯学) ( 1994年3月   昭和大学 )

研究分野

  • ライフサイエンス / 発生生物学

経歴(researchmap)

  • 新潟大学 歯学部 教授

    2016年 - 現在

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  • 新潟大学 歯学部 准教授

    2013年 - 2015年

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  • 英国 King’s College London Principal investigator (PI)

    2006年 - 2013年

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  • 英国King’s College London Senior research fellow

    2005年 - 2006年

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経歴

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   教授

    2016年1月 - 現在

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 摂食環境制御学   准教授

    2013年11月 - 2015年12月

 

論文

  • マイクロRNAは顎顔面形成において老化シグナルを抑制している

    サリ・フィンサ, ヴァネッサ・ウタマ, 川崎 勝盛, 川崎 真依子, 丹原 惇, 大澤 知朗, 工藤 武久, 北村 円, 前田 健康, 大峡 淳

    新潟歯学会雑誌   53 ( 2 )   98 - 98   2024年1月

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    記述言語:英語   出版者・発行元:新潟歯学会  

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  • Loss of Autophagy Disrupts Stemness of Ameloblast-Lineage Cells in Aging. 査読 国際誌

    H Ida-Yonemochi, K Otsu, T Irié, A Ohazama, H Harada, H Ohshima

    Journal of dental research   220345231209931 - 220345231209931   2023年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autophagy is one of the intracellular degradation pathways and maintains cellular homeostasis, regulating the stress response, cell proliferation, and signal transduction. To elucidate the role of autophagy in the maintenance of dental epithelial stem cells and the subsequent enamel formation, we analyzed autophagy-deficient mice in epithelial cells (Atg7f/f;KRT14-Cre mice), focusing on the influence of aging and stress environments. We also performed in vitro cell and organ culture experiments with an autophagy inhibitor. In young Atg7f/f;KRT14-Cre mice, morphological change was not obvious in maxillary incisors, except for the remarkable cell death in the stratum intermedium of the transitional stage. However, under stress conditions of hyperglycemia, the incisor color changed to white in diabetes Atg7f/f;KRT14-Cre mice. Regarding dental epithelial stem cells, the shape of the apical bud region of the incisor became irregular with age, and odontoma was formed in aged Atg7f/f;KRT14-Cre mice. In addition, the shape of apical bud culture cells of Atg7f/f;KRT14-Cre mice became irregular and enlarged atypically, with epigenetic changes during culture, suggesting that autophagy deficiency may induce tumorigenesis in dental epithelial cells. The epigenetic change and upregulation of p21 expression were induced by autophagy inhibition in vivo and in vitro. These findings suggest that autophagy is important for the regulation of stem cell maintenance, proliferation, and differentiation of ameloblast-lineage cells, and an autophagy disorder may induce tumorigenesis in odontogenic epithelial cells.

    DOI: 10.1177/00220345231209931

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  • Ift88はShhシグナル経路を介してエナメル形成を調節する

    工藤 武久, 丹原 惇, 北村 円, 大峡 淳, 齋藤 功

    甲北信越矯正歯科学会雑誌   31 ( 1 )   65 - 65   2023年6月

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    記述言語:日本語   出版者・発行元:甲北信越矯正歯科学会  

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  • A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment. 査読 国際誌

    Piranit Kantaputra, Niramol Leelaadisorn, Athiwat Hatsadaloi, Natalina Quarto, Worrachet Intachai, Sissades Tongsima, Katsushige Kawasaki, Atsushi Ohazama, Chumpol Ngamphiw, Paswach Wiriyakijja

    Diagnostics (Basel, Switzerland)   13 ( 5 )   2023年2月

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    記述言語:英語  

    BACKGROUND: Enamel knots and Hertwig epithelial root sheath (HERS) regulate the growth and folding of the dental epithelium, which subsequently determines the final form of tooth crown and roots. We would like to investigate the genetic etiology of seven patients affected with unique clinical manifestations, including multiple supernumerary cusps, single prominent premolars, and single-rooted molars. METHODS: Oral and radiographic examination and whole-exome or Sanger sequencing were performed in seven patients. Immunohistochemical study during early tooth development in mice was performed. RESULTS: A heterozygous variant (c. 865A>G; p.Ile289Val) in CACNA1S was identified in all the patients, but not in an unaffected family member and control. Immunohistochemical study showed high expression of Cacna1s in the secondary enamel knot. CONCLUSIONS: This CACNA1S variant seemed to cause impaired dental epithelial folding; too much folding in the molars and less folding in the premolars; and delayed folding (invagination) of HERS, which resulted in single-rooted molars or taurodontism. Our observation suggests that the mutation in CACNA1S might disrupt calcium influx, resulting in impaired dental epithelium folding, and subsequent abnormal crown and root morphology.

    DOI: 10.3390/diagnostics13050895

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  • Ift88 regulates enamel formation via involving Shh signaling. 査読 国際誌

    Takehisa Kudo, Maiko Kawasaki, Katsushige Kawasaki, Fumiya Meguro, Jun Nihara, Izumi Honda, Madoka Kitamura, Akira Fujita, Kazuaki Osawa, Kaya Ichikawa, Takahiro Nagai, Yoko Ishida, Paul T Sharpe, Takeyasu Maeda, Isao Saito, Atsushi Ohazama

    Oral diseases   29 ( 4 )   1622 - 1631   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: The ciliopathies are a wide spectrum of human diseases, which are caused by perturbations in the function of primary cilia. Tooth enamel anomalies are often seen in ciliopathy patients; however, the role of primary cilia in enamel formation remains unclear. MATERIALS AND METHODS: We examined mice with epithelial conditional deletion of the ciliary protein, Ift88, (Ift88fl / fl ;K14Cre). RESULTS: Ift88fl / fl ;K14Cre mice showed premature abrasion in molars. A pattern of enamel rods which is determined at secretory stage, was disorganized in Ift88 mutant molars. Many amelogenesis-related molecules expressing at the secretory stage, including amelogenin and ameloblastin, enamelin, showed significant downregulation in Ift88 mutant molar tooth germs. Shh signaling is essential for amelogenesis, which was found to be downregulated in Ift88 mutant molar at the secretory stage. Application of Shh signaling agonist at the secretory stage partially rescued enamel anomalies in Ift88 mutant mice. CONCLUSION: Findings in the present study indicate that the function of the primary cilia via Ift88 is critical for the secretory stage of amelogenesis through involving Shh signaling.

    DOI: 10.1111/odi.14162

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  • Expression of R-spondins/Lgrs in development of movable craniofacial organs. 査読 国際誌

    Jun Nihara, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Fumiya Meguro, Takehisa Kudo, Supaluk Trakanant, Takahiro Nagai, Isao Saito, Takeyasu Maeda, Atsushi Ohazama

    Gene expression patterns : GEP   41   119195 - 119195   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Wnt signaling plays a critical role in the development of many organs, including the major movable craniofacial organs tongue, lip, and eyelid. Four members of the R-spondin family (Rspo1-4) bind to Lgr4/5/6 to regulate the activation of Wnt signaling. However, it is not fully understood how Rspos/Lgrs regulate Wnt signaling during the development of movable craniofacial organs. To address this question, we examined the expression of Rspos, Lgrs, and Axin2 (major mediator of canonical Wnt signaling) during tongue, lip, and eyelid development. The expression of Axin2, Rspos and Lgrs was observed in many similar regions, suggesting that Rspos likely activate canonical Wnt signaling through the Lgr-dependent pathway in these regions. Lgr expression was not detected in regions where Axin2 and Rspos were expressed, suggesting that Rspos might activate canonical Wnt signaling through the Lgr-independent pathway in these regions. In addition, the expression of Rspos and Lgrs were observed in some other regions where Axin2 was not expressed, suggesting the possibility that Rspos and/or Lgrs are involved in non-canonical Wnt signaling or the Wnt-independent pathway. Thus, we identified a dynamic spatiotemporal expression pattern of Rspos and Lgrs during the development of the eyelid, tongue, and lip.

    DOI: 10.1016/j.gep.2021.119195

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  • Perivascular Hedgehog responsive cells play a critical role in peripheral nerve regeneration via controlling angiogenesis. 査読 国際誌

    Yurie Yamada, Jun Nihara, Supaluk Trakanant, Takehisa Kudo, Kenji Seo, Izumi Iida, Kenji Izumi, Masayuki Kurose, Yutaka Shimomura, Miho Terunuma, Takeyasu Maeda, Atsushi Ohazama

    Neuroscience research   173   62 - 70   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hh signaling has been shown to be activated in intact and injured peripheral nerve. However, the role of Hh signaling in peripheral nerve is not fully understood. In the present study, we observed that Hh signaling responsive cells [Gli1(+) cells] in both the perineurium and endoneurium. In the endoneurium, Gli1(+) cells were classified as blood vessel associated or non-associated. After injury, Gli1(+) cells around blood vessels mainly proliferated to then accumulate into the injury site along with endothelial cells. Hh signaling activity was retained in Gli1(+) cells during nerve regeneration. To understand the role of Hedgehog signaling in Gli1(+) cells during nerve regeneration, we examined mice with Gli1(+) cells-specific inactivation of Hh signaling (Smo cKO). After injury, Smo cKO mice showed significantly reduced numbers of accumulated Gli1(+) cells along with disorganized vascularization at an early stage of nerve regeneration, which subsequently led to an abnormal extension of the axon. Thus, Hh signaling in Gli1(+) cells appears to be involved in nerve regeneration through controlling new blood vessel formation at an early stage.

    DOI: 10.1016/j.neures.2021.06.003

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  • MicroRNAs regulate distal region of mandibular development through Hh signaling 査読

    Supaluk Trakanant, Jun Nihara, Takahiro Nagai, Maiko Kawasaki, Katsushige Kawasaki, Yoko Ishida, Fumiya Meguro, Takehisa Kudo, Akane Yamada, Takeyasu Maeda, Isao Saito, Atsushi Ohazama

    JOURNAL OF ANATOMY   238 ( 3 )   711 - 719   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Mandibular anomalies are often seen in various congenital diseases, indicating that mandibular development is under strict molecular control. Therefore, it is crucial to understand the molecular mechanisms involved in mandibular development. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating the level of gene expression. We found that the mesenchymal conditional deletion of miRNAs arising from a lack ofDicer(an essential molecule for miRNA processing,Dicer(fl)(/)(fl);Wnt1Cre), led to an abnormal groove formation at the distal end of developing mandibles. At E10.5, when the region forms, inhibitors of Hh signaling,Ptch1andHhip1showed increased expression at the region inDicermutant mandibles, whileGli1(a major mediator of Hh signaling) was significantly downregulated in mutant mandibles. These suggest that Hh signaling was downregulated at the distal end ofDicermutant mandibles by increased inhibitors. To understand whether the abnormal groove formation inDicermutant mandibles was caused by the downregulation of Hh signaling, mice with a mesenchymal deletion of Hh signaling activity arising from a lack ofSmo(an essential molecule for Hh signaling activation,Smo(fl)(/)(fl);Wnt1Cre) were examined.Smo(fl)(/)(fl);Wnt1Cremice showed a similar phenotype in the distal region of their mandibles to those inDicer(fl)(/)(fl);Wnt1Cremice. We also found that approximately 400 miRNAs were expressed in wild-type mandibular mesenchymes at E10.5, and six microRNAs were identified as miRNAs with binding potential against bothPtch1andHhip1. Their expressions at the distal end of the mandible were confirmed byin situhybridization. This indicates that microRNAs regulate the distal part of mandibular formation at an early stage of development by involving Hh signaling activity through controlling its inhibitor expression level.

    DOI: 10.1111/joa.13328

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  • A novel P3H1 mutation is associated with osteogenesis imperfecta type VIII and dental anomalies. 査読 国際誌

    Piranit Nik Kantaputra, Prapai Dejkhamron, Worrachet Intachai, Chumpol Ngamphiw, James R Ketudat Cairns, Katsushige Kawasaki, Atsushi Ohazama, Bjorn Olsen, Sissades Tongsima, Salita Angkurawaranon

    Oral surgery, oral medicine, oral pathology and oral radiology   132 ( 6 )   4564 - 4564   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Our objective was to investigate the molecular etiology of osteogenesis imperfecta type VIII and dental anomalies in 4 siblings of a Karen tribe family. MATERIALS AND METHODS: Four patients and their unaffected parents were studied by clinical and radiographic examination. In situ hybridization of P3h1 during early murine tooth development, whole-exome sequencing, and Sanger direct sequencing were performed. RESULTS: A novel homozygous missense P3H1 mutation (NM_001243246.1; c.2141A>G; NP_001230175.1; p.Lys714Arg) was identified in all patients. Their unaffected parents were heterozygous for the mutation. The mutation is hypothesized to belong to isoform c of P3H1. Mutations in P3H1 are associated with autosomal recessive osteogenesis imperfecta type VIII. Hypodontia, a mesiodens, and single-rooted permanent second molars found in our patients have never been reported in patients with P3H1 mutations. Single-rooted second permanent molars or failure to form multiple roots implies effects of the P3H1 mutation on root development. CONCLUSIONS: We report a novel P3H1 mutation as the underlying cause of osteogenesis imperfecta type VIII with dental anomalies. Our study suggests that isoform c of P3H1 is also a functional isoform of P3H1. We report, for the first time, to our knowledge, the association of P3H1 mutation and osteogenesis imperfecta type VIII with dental anomalies.

    DOI: 10.1016/j.oooo.2021.01.023

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  • R2TP/PAQosome as a promising chemotherapeutic target in cancer. 査読 国際誌

    Yoshito Kakihara, Tetsuo Kiguchi, Atsushi Ohazama, Makio Saeki

    The Japanese dental science review   56 ( 1 )   38 - 42   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    R2TP/PAQosome (particle for arrangement of quaternary structure) is a novel multisubunit chaperone specialized in the assembly/maturation of protein complexes that are involved in essential cellular processes such as PIKKs (phosphatidylinositol 3-kinase-like kinases) signaling, snoRNP (small nucleolar ribonucleoprotein) biogenesis, and RNAP II (RNA polymerase II) complex formation. In this review article, we describe the current understanding of R2TP/PAQosome functions and characteristics as well as how the chaperone complex is involved in oncogenesis, highlighting DNA damage response, mTOR (mammalian target of rapamycin) pathway as well as snoRNP biogenesis. Also, we discuss its possible involvement in HNSCC (head and neck squamous cell carcinoma) including OSCC (oral squamous cell carcinoma). Finally, we provide an overview of current anti-cancer drug development efforts targeting R2TP/PAQosome.

    DOI: 10.1016/j.jdsr.2019.08.001

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  • Reptinは胎仔上皮におけるDNA損傷応答を介して器官形成を制御する

    目黒 史也, 柿原 嘉人, 川崎 真依子, 川崎 勝盛, 丹原 惇, トゥラカナン・スッパラック, 工藤 武久, 山田 茜, 前田 健康, 多部田 康一, 佐伯 万騎男, 大峡 淳

    新潟歯学会雑誌   50 ( 2 )   115 - 116   2020年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Changes in signalling pathways in the palatal cleft in CL/Fr mice

    Akane Yamada, Takahiro Nagai, Atsushi Kitamura, Maiko Kawasaki, Katsushige Kawasaki, Yasumitsu Kodama, Takeyasu Maeda, Atsushi Ohazama, Ritsuo Takagi

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY MEDICINE AND PATHOLOGY   32 ( 5 )   331 - 335   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Cleft palate is one of the most common congenital diseases. Therefore, elucidating the molecular mechanisms of palate development is crucial for basic science and the clinical field. Cleft palate in mouse with targeted gene mutation is an excellent experimental model for clarifying the mechanisms driving palate development. Cleft palate occurs in two forms: a cleft between the primary and secondary palates (primary cleft palate) and a cleft between the secondary palates (secondary cleft palate). It remains unclear whether primary palate development is under similar molecular control as secondary palate formation, since most of studies have focused on secondary palate development using mutant mice. CL/Fraser (CL/Fr) is a mouse strain that often exhibits spontaneous primary cleft palate; however, the molecular changes in primary cleft palate in CL/Fr mice are not fully understood. Several signaling pathways, including Shh, Fgf, Bmp, and Wnt signaling, have been shown to play key roles in secondary palate development. In the present study, we found that Shh and Wnt signaling pathways were downregulated in the primary cleft palate region in CL/Fr mice.

    DOI: 10.1016/j.ajoms.2019.12.001

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  • Overactivation of the NF-κB pathway impairs molar enamel formation. 査読 国際誌

    Akane Yamada, Maiko Kawasaki, Yasuo Miake, Yurie Yamada, James Blackburn, Kataushige Kawasaki, Supaluk Trakanant, Takahiro Nagai, Jun Nihara, Takehisa Kudo, Fumiya Meguro, Ruth Schmidt-Ullrich, Bigang Liu, Yinling Hu, Angustias Page, Ángel Ramírez, Paul T Sharpe, Takeyasu Maeda, Ritsuo Takagi, Atsushi Ohazama

    Oral diseases   26 ( 7 )   1513 - 1522   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm-derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF-κB pathway is known to be responsible for HED, it remains unclear whether this pathway is involved in the process of enamel formation. EXPERIMENTAL SUBJECTS AND METHODS: To address this question, we examined the mice overexpressing Ikkβ (an essential component required for the activation of NF-κB pathway) under the keratin 5 promoter (K5-Ikkβ). RESULTS: Upregulation of the NF-κB pathway was confirmed in the ameloblasts of K5-Ikkβ mice. Premature abrasion was observed in the molars of K5-Ikkβ mice, which was accompanied by less mineralized enamel. However, no significant changes were observed in the enamel thickness and the pattern of enamel rods in K5-Ikkβ mice. Klk4 expression was significantly upregulated in the ameloblasts of K5-Ikkβ mice at the maturation stage, and the expression of its substrate, amelogenin, was remarkably reduced. This suggests that abnormal enamel observed in K5-Ikkβ mice was likely due to the compromised degradation of enamel protein at the maturation stage. CONCLUSION: Therefore, we could conclude that the overactivation of the NF-κB pathway impairs the process of amelogenesis.

    DOI: 10.1111/odi.13384

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  • Gli3 is a Key Factor in the Schwann Cells from Both Intact and Injured Peripheral Nerves. 査読 国際誌

    Yurie Yamada, Supaluk Trakanant, Jun Nihara, Takehisa Kudo, Kenji Seo, Makio Saeki, Masayuki Kurose, Daisuke Matsumaru, Takeyasu Maeda, Atsushi Ohazama

    Neuroscience   432   229 - 239   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hedgehog (Hh) signaling has been shown to be involved in regulating both intact and injured peripheral nerves. Therefore, it is critical to understand how Hh signaling is regulated in the peripheral nerve. One of the transcription factors of the Hh signaling pathway, Gli3, functions as both a repressor and an activator of Hh signaling activity. However, it remains unclear whether Gli3 is involved in controlling the intact and/or injured peripheral nerves. We found that Gli3 act as a repressor in the Schwann cells (SCs) of intact sciatic nerves. Although Dhh and Ptch1 expression were present, Hh signaling was not activated in these SCs. Moreover, heterozygous Gli3 mutation (Gli3-/+) induced ectopic Hh signaling activity in SCs. Hh signaling was thus suppressed by Gli3 in the SCs of intact sciatic nerves. Minor morphological changes were observed in the intact nerves from Gli3-/+ mice. Gli3 expression was significantly decreased following injury and ligand expression switched from Dhh to Shh, which activated Hh signaling in SCs from wild-type mice. Changes of these ligands was found to be important for nerve regeneration in which the downregulation of Gli3 was also involved. In fact, Gli3-/+ mice exhibited accelerated ligand switching and subsequent nerve regeneration. Both suppression of Hh signaling with Gli3 in the intact nerves and activation of Hh signaling without Gli3 in the injured nerve were observed in the SCs in an autocrine manner. Thus, Gli3 is a key factor in the control of intact peripheral nerve homeostasis and nerve regeneration.

    DOI: 10.1016/j.neuroscience.2020.02.036

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  • Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2. 査読 国際誌

    Piranit Nik Kantaputra, Prapai Dejkhamron, Worrachet Intachai, Chumpol Ngamphiw, Katsushige Kawasaki, Atsushi Ohazama, Suttichai Krisanaprakornkit, Bjorn Olsen, Sissades Tongsima, Jame R Ketudat Cairns

    European journal of orthodontics   43 ( 1 )   45 - 50   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. OBJECTIVE: To report for the first time the molecular aetiology of JHS. PATIENT AND METHODS: Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. RESULTS: Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. CONCLUSIONS: Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.

    DOI: 10.1093/ejo/cjaa023

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  • Clouston syndrome with pili canaliculi, pili torti, overgrown hyponychium, onycholysis, taurodontism and absence of palmoplantar keratoderma. 査読 国際誌

    Piranit Kantaputra, Worrachet Intachai, Katsushige Kawasaki, Atsushi Ohazama, Bruce Carlson, Natalina Quarto, Chulabhorn Pruksachatkun, Mati Chuamanochan

    The Journal of dermatology   47 ( 6 )   e230-e232   2020年3月

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  • Molecular mechanisms in palatal rugae development. 査読 国際誌

    Supaluk Trakanant, Jun Nihara, Maiko Kawasaki, Fumiya Meguro, Akane Yamada, Katsushige Kawasaki, Isao Saito, Maeda Takeyasu, Atsushi Ohazama

    Journal of oral biosciences   62 ( 1 )   30 - 35   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structures helps to elucidate the genetic commonality of developmental processes, as organs with these structures are believed to share the same molecular mechanisms and fundamental processes. Palatal rugae are periodic corrugated structures on the hard palate and are conserved in all mammals. Although the numbers and patterns of the palatal rugae are species specific, they are consistent in each mammalian species, except humans. HIGHLIGHT: Palatal rugae development is thus under strict genetic control in most mammals and is an excellent model to investigate the genetic commonality of developmental processes to form periodic patterning. CONCLUSION: This review highlights the current understanding of the molecular mechanisms of palatal rugae development.

    DOI: 10.1016/j.job.2019.12.002

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  • Ift88 is involved in mandibular development. 査読 国際誌

    Atsushi Kitamura, Maiko Kawasaki, Katsushige Kawasaki, Fumiya Meguro, Akane Yamada, Takahiro Nagai, Yasumitsu Kodama, Supaluk Trakanant, Paul T Sharpe, Takeyasu Maeda, Ritsuo Takagi, Atsushi Ohazama

    Journal of anatomy   236 ( 2 )   317 - 324   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The mandible is a crucial organ in both clinical and biological fields due to the high frequency of congenital anomalies and the significant morphological changes during evolution. Primary cilia play a critical role in many biological processes, including the determination of left/right axis patterning, the regulation of signaling pathways, and the formation of bone and cartilage. Perturbations in the function of primary cilia are known to cause a wide spectrum of human diseases: the ciliopathies. Craniofacial dysmorphologies, including mandibular deformity, are often seen in patients with ciliopathies. Mandibular development is characterized by chondrogenesis and osteogenesis; however, the role of primary cilia in mandibular development is not fully understood. To address this question, we generated mice with mesenchymal deletions of the ciliary protein, Ift88 (Ift88fl/fl ;Wnt1Cre). Ift88fl/fl ;Wnt1Cre mice showed ectopic mandibular bone formation, whereas Ift88 mutant mandible was slightly shortened. Meckel's cartilage was modestly expanded in Ift88fl/fl ;Wnt1Cre mice. The downregulation of Hh signaling was found in most of the mesenchyme of Ift88 mutant mandible. However, mice with a mesenchymal deletion of an essential molecule for Hh signaling activity, Smo (Smofl/fl ;Wnt1Cre), showed only ectopic mandibular formation, whereas Smo mutant mandible was significantly shortened. Ift88 is thus involved in chondrogenesis and osteogenesis during mandibular development, partially through regulating Sonic hedgehog (Shh) signaling.

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  • Primary cilia in murine palatal rugae development. 査読 国際誌

    Mayuko Nakaniwa, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Fumiya Meguro, Maeda Takeyasu, Atsushi Ohazama

    Gene expression patterns : GEP   34   119062 - 119062   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Periodic patterning of iterative structures is a fundamental process during embryonic development, since these structures are diverse across the animal kingdom. Therefore, elucidating the molecular mechanisms in the formation of these structures promotes understanding of the process of organogenesis. Periodically patterned ridges, palatal rugae (situated on the hard palate of mammals), are an excellent experimental model to clarify the molecular mechanisms involved in the formation of periodic patterning of iterative structures. Primary cilia are involved in many biological events, including the regulation of signaling pathways such as Shh and non-canonical Wnt signaling. However, the role of primary cilia in the development of palatal rugae remains unclear. We found that primary cilia were localized to the oral cavity side of the interplacode epithelium of the palatal rugae, whereas restricted localization of primary cilia could not be detected in other regions. Next, we generated mice with a placodal conditional deletion of the primary cilia protein Ift88, using ShhCre mice (Ift88 fl/fl;ShhCre). Highly disorganized palatal rugae were observed in Ift88 fl/fl;ShhCre mice. Furthermore, by comparative in situ hybridization analysis, many Shh and non-canonical Wnt signaling-related molecules showed spatiotemporal expression patterns during palatal rugae development, including restricted expression in the epithelium (placodes and interplacodes) and mesenchyme. Some of these expression were found to be altered in Ift88 fl/fl;ShhCre mice. Primary cilia is thus involved in development of palatal rugae.

    DOI: 10.1016/j.gep.2019.119062

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  • Bmp signaling in molar cusp formation. 査読 国際誌

    Fumiya Meguro, Thantrira Porntaveetus, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Yoshito Kakihara, Makio Saeki, Koichi Tabeta, John A Kessler, Takeyasu Maeda, Atsushi Ohazama

    Gene expression patterns : GEP   32   67 - 71   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.

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  • 下歯槽神経再生における血管内皮細胞増殖因子の関与について

    西田 洋平, 山田 友里恵, 大峡 淳, 前田 健康, 瀬尾 憲司

    新潟歯学会雑誌   49 ( 1 )   38 - 38   2019年6月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Ift88 limits bone formation in maxillary process through suppressing apoptosis. 査読 国際誌

    Momoko Watanabe, Maiko Kawasaki, Katsushige Kawasaki, Atsushi Kitamura, Takahiro Nagai, Yasumitsu Kodama, Fumiya Meguro, Akane Yamada, Paul T Sharpe, Takeyasu Maeda, Ritsuo Takagi, Atsushi Ohazama

    Archives of oral biology   101   43 - 50   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The development of the maxillary bone is under strict molecular control because of its complicated structure. Primary cilia play a critical role in craniofacial development, since defects in primary cilia are known to cause congenital craniofacial dysmorphologies as a wide spectrum of human diseases: the ciliopathies. The primary cilia also are known to regulate bone formation. However, the role of the primary cilia in maxillary bone development is not fully understood. DESIGN: To address this question, we generated mice with a mesenchymal conditional deletion ofIft88 using the Wnt1Cre mice (Ift88fl/fl;Wnt1Cre). The gene Ift88 encodes a protein that is required for the function and formation of primary cilia. RESULTS: It has been shown thatIft88fl/fl;Wnt1Cre mice exhibit cleft palate. Here, we additionally observed excess bone formation in the Ift88 mutant maxillary process. We also found ectopic apoptosis in the Ift88 mutant maxillary process at an early stage of development. To investigate whether the ectopic apoptosis is related to the Ift88 mouse maxillary phenotypes, we generated Ift88fl/fl;Wnt1Cre;p53-/- mutants to reduce apoptosis. The Ift88fl/fl;Wnt1Cre;p53-/- mice showed no excess bone formation, suggesting that the cells evading apoptosis by the presence of Ift88 in wild-type mice limit bone formation in maxillary development. On the other hand, the palatal cleft was retained in the Ift88fl/fl;Wnt1Cre;p53-/- mice, indicating that the excess bone formation or abnormal apoptosis was independent of the cleft palate phenotype in Ift88 mutant mice. CONCLUSIONS: Ift88 limits bone formation in the maxillary process by suppressing apoptosis.

    DOI: 10.1016/j.archoralbio.2019.02.017

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  • ADAMTSL1 and mandibular prognathism. 査読 国際誌

    Piranit N Kantaputra, Apitchaya Pruksametanan, Nattapol Phondee, Athiwat Hutsadaloi, Worrachet Intachai, Katsushig Kawasaki, Atsushi Ohazama, Chumpol Ngamphiw, Sissades Tongsima, James R Ketudat Cairns, Polbhat Tripuwabhrut

    Clinical genetics   95 ( 4 )   507 - 515   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mandibular prognathism is characterized by a prognathic or prominent mandible. The objective of this study was to find the gene responsible for mandibular prognathism. Whole exome sequencing analysis of a Thai family (family 1) identified the ADAMTSL1 c.176C>A variant as the potential defect. We cross-checked our exome data of 215 people for rare variants in ADAMTSL1 and found that the c.670C>G variant was associated with mandibular prognathism in families 2 and 4. Mutation analysis of ADAMTSL1 in 79 unrelated patients revealed the c.670C>G variant was also found in family 3. We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible. Adamtsl1 is strongly expressed in the condensed mesenchymal cells of the mouse condyle, but not at the cartilage of the long bones. This explains why the patients with ADAMTSL1 mutations had abnormal mandibles but normal long bones. This is the first report that mutations in ADAMTSL1 are responsible for the pathogenesis of mandibular prognathism.

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  • Semaphorin 3A Inhibits Nerve Regeneration During Early Stage after Inferior Alveolar Nerve Transection. 査読 国際誌

    Hiroko Kanemaru, Yurie Yamada, Atsushi Ohazama, Takeyasu Maeda, Kenji Seo

    Scientific reports   9 ( 1 )   4245 - 4245   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuroma formation at sites of injury can impair peripheral nerve regeneration. Although the involvement of semaphorin 3A has been suggested in neuroma formation, this detailed process after injury is not fully understood. This study was therefore undertaken to examine the effects of semaphorin 3A on peripheral nerve regeneration during the early stage after injury. Immunohistochemistry for semaphorin 3A and PGP9.5, a general neuronal marker, was carried out for clarify chronological changes in their expressions after transection of the mouse inferior alveolar nerve thorough postoperative days 1 to 7. At postoperative day 1, the proximal stump of the damaged IAN exhibited semaphorin 3A, while the distal stump lacked any immunoreactivity. From this day on, its expression lessened, ultimately disappearing completely in all regions of the transected inferior alveolar nerve. A local administration of an antibody to semaphorin 3A into the nerve transection site at postoperative day 3 inhibited axon sprouting at the injury site. This antibody injection increased the number of trigeminal ganglion neurons labeled with DiI (paired t-test, p < 0.05). Immunoreactivity of the semaphorin 3A receptor, neuropilin-1, was also detected at the proximal stump at postoperative day 1. These results suggest that nerve injury initiates semaphorin 3A production in ganglion neurons, which is then delivered through the nerve fibers to the proximal end, thereby contributes to the inhibition of axonal sprouting from the proximal region of injured nerves in the distal direction. To our knowledge, this is the first report to reveal the involvement of Sema3A in the nerve regeneration process at its early stage.

    DOI: 10.1038/s41598-018-37819-6

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  • MicroRNAs control eyelid development through regulating Wnt signaling. 査読 国際誌

    Takahiro Nagai, Supaluk Trakanant, Maiko Kawasaki, Katsushige Kawasaki, Yurie Yamada, Momoko Watanabe, James Blackburn, Yoko Otsuka-Tanaka, Mitsue Hishinuma, Atsushi Kitatmura, Fumiya Meguro, Akane Yamada, Yasumitsu Kodama, Takeyasu Maeda, Qiliang Zhou, Yasuo Saijo, Akihiro Yasue, Paul T Sharpe, Robert Hindges, Ritsuo Takagi, Atsushi Ohazama

    Developmental dynamics : an official publication of the American Association of Anatomists   248 ( 3 )   201 - 210   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The timing, location, and level of gene expression are crucial for normal organ development, because morphogenesis requires strict genetic control. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating gene expression level. Although miRNAs are known to be involved in many biological events, the role of miRNAs in organogenesis is not fully understood. Mammalian eyelids fuse and separate during development and growth. In mice, failure of this process results in the eye-open at birth (EOB) phenotype. RESULTS: It has been shown that conditional deletion of mesenchymal Dicer (an essential protein for miRNA processing; Dicer fl/fl ;Wnt1Cre) leads to the EOB phenotype with full penetrance. Here, we identified that the up-regulation of Wnt signaling resulted in the EOB phenotype in Dicer mutants. Down-regulation of Fgf signaling observed in Dicer mutants was caused by an inverse relationship between Fgf and Wnt signaling. Shh and Bmp signaling were down-regulated as the secondary effects in Dicer fl/fl ;Wnt1Cre mice. Wnt, Shh, and Fgf signaling were also found to mediate the epithelial-mesenchymal interactions in eyelid development. CONCLUSIONS: miRNAs control eyelid development through Wnt. Developmental Dynamics 248:201-210, 2019. © 2019 Wiley Periodicals, Inc.

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  • The Sonic Hedgehog signaling pathway regulates inferior alveolar nerve regeneration. 査読 国際誌

    Yurie Yamada, Atsushi Ohazama, Takeyasu Maeda, Kenji Seo

    Neuroscience letters   671   114 - 119   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Activation of Shh signaling is known to be observed following injury of the peripheral nerves such as the sciatic nerve. However, the precise role of Shh signaling during peripheral nerve regeneration is not fully understood. The inferior alveolar nerve (IAN) is most commonly injured during oral surgery. Unlike the sciatic nerve, the IAN is isolated from other craniofacial tissues, as it resides in a long bony canal within the mandible. The IAN is thus an excellent experimental model for investigating peripheral nerve regeneration. In this study, the role of Shh signaling in peripheral nerve regeneration was investigated using the mouse IAN transection model. During regeneration, Shh signaling was activated within the entire distal region of the IAN and proximal stumps. Inhibition of Shh signaling by cyclopamine application at the transection site led to abnormal axon growth in random directions, a reduced number of macrophages, and an increase in myelin debris within the distal region. Shh signaling is thus involved in peripheral nerve regeneration via the regulation of myelin degradation.

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  • Expanding the Oro-Dental and Mutational Spectra of Kabuki Syndrome and Expression of KMT2D and KDM6A in Human Tooth Germs. 査読 国際誌

    Thantrira Porntaveetus, Mushriq F Abid, Thanakorn Theerapanon, Chalurmpon Srichomthong, Atsushi Ohazama, Katsushige Kawasaki, Maiko Kawasaki, Kanya Suphapeetiporn, Paul T Sharpe, Vorasuk Shotelersuk

    International journal of biological sciences   14 ( 4 )   381 - 389   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of KMT2D (histone-lysine N-methyltransferase 2D) or KDM6A (lysine-specific demethylase 6A) genes in tooth development have not been well defined. Here, we report seven unrelated Thai patients with Kabuki syndrome having congenital absence of teeth, malocclusion, high-arched palate, micrognathia, and deviated tooth shape and size. Exome sequencing successfully identified that six patients were heterozygous for mutations in KMT2D, and one in KDM6A. Six were novel mutations, of which five were in KMT2D and one in KDM6A. They were truncating mutations including four frameshift deletions and two nonsense mutations. The predicted non-functional KMT2D and KDM6A proteins are expected to cause disease by haploinsufficiency. Our study expands oro-dental, medical, and mutational spectra associated with Kabuki syndrome. We also demonstrate for the first time that KMT2D and KDM6A are expressed in the dental epithelium of human tooth germs.

    DOI: 10.7150/ijbs.23517

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  • Lrp4/Wise regulates palatal rugae development through Turing-type reaction-diffusion mechanisms. 査読 国際誌

    Maiko Kawasaki, Katsushige Kawasaki, Fumiya Meguro, Akane Yamada, Ryuichi Ishikawa, Thantrira Porntaveetus, James Blackburn, Yoko Otsuka-Tanaka, Naoaki Saito, Masato S Ota, Paul T Sharpe, John A Kessler, Joachim Herz, Martyn T Cobourne, Takeyasu Maeda, Atsushi Ohazama

    PloS one   13 ( 9 )   e0204126   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structure helps to elucidate the process of organogenesis. Turing-type reaction-diffusion mechanisms have been shown to play a critical role in regulating periodic patterning in organogenesis. Palatal rugae are periodically patterned ridges situated on the hard palate of mammals. We have previously shown that the palatal rugae develop by a Turing-type reaction-diffusion mechanism, which is reliant upon Shh (as an inhibitor) and Fgf (as an activator) signaling for appropriate organization of these structures. The disturbance of Shh and Fgf signaling lead to disorganized palatal rugae. However, the mechanism itself is not fully understood. Here we found that Lrp4 (transmembrane protein) was expressed in a complementary pattern to Wise (a secreted BMP antagonist and Wnt modulator) expression in palatal rugae development, representing Lrp4 expression in developing rugae and Wise in the inter-rugal epithelium. Highly disorganized palatal rugae was observed in both Wise and Lrp4 mutant mice, and these mutants also showed the downregulation of Shh signaling, which was accompanied with upregulation of Fgf signaling. Wise and Lrp4 are thus likely to control palatal rugae development by regulating reaction-diffusion mechanisms through Shh and Fgf signaling. We also found that Bmp and Wnt signaling were partially involved in this mechanism.

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  • Sox Genes Show Spatiotemporal Expression during Murine Tongue and Eyelid Development. 査読 国際誌

    Ryuichi Ishikawa, Maiko Kawasaki, Katsushige Kawasaki, Akane Yamada, Supaluk Trakanant, Fumiya Meguro, Atsushi Kitamura, Takehisa Kudo, Takeyasu Maeda, Atsushi Ohazama

    International journal of dentistry   2018 ( 10 )   1601363 - 1601363   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The tongue is a critical organ, involved in functions such as speaking, swallowing, mastication, and degustation. Although Sox genes are known to play critical roles in many biological processes, including organogenesis, the expression of the Sox family members during tongue development remains unclear. We therefore performed a comparative in situ hybridization analysis of 17 Sox genes (Sox1-14, 17, 18, and 21) during murine tongue development. Sox2, 4, 6, 8, 9, 10, 11, 12, and 21 were found to be expressed in the tongue epithelium, whereas Sox2, 4-6, 8-11, 13, and 21 showed expression in the mesenchyme of the developing tongue. Expression of Sox1, 4, 6, 8-12, and 21 were observed in the developing tongue muscle. Sox5 and 13 showed expression only at E12, while Sox1 expression was observed only on E18. Sox6, 8, 9, and 12 showed expression at several stages. Although the expression of Sox2, 4, 10, 11, and 21 was detected during all the four stages of tongue development, their expression patterns differed among the stages. We thus identified a dynamic spatiotemporal expression pattern of the Sox genes during murine tongue development. To understand whether Sox genes are involved in the development of other craniofacial organs through similar roles to those in tongue development, we also examined the expression of Sox genes in eyelid primordia, which also contain epithelium, mesenchyme, and muscle. However, expression patterns and timing of Sox genes differed between tongue and eyelid development. Sox genes are thus related to organogenesis through different functions in each craniofacial organ.

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  • Vascularization via activation of VEGF-VEGFR signaling is essential for peripheral nerve regeneration. 査読

    Yohei Nishida, Yurie Yamada, Hiroko Kanemaru, Atsushi Ohazama, Takeyasu Maeda, Kenji Seo

    Biomedical research (Tokyo, Japan)   39 ( 6 )   287 - 294   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peripheral nerve injury has been suggested to up-regulate mRNA for the vascular endothelial growth factor (VEGF) which enhances nerve regeneration. VEGF is known to regulate angiogenesis by binding with a specific receptor, the vascular endothelial growth factor receptor (VEGFR). However, little is known about the involvement of VEGF-VEGFR signaling in the nerve regeneration at early stages though previous studies contained a lengthy observation. The present study examined that relationship between angiogenesis and peripheral nerve regeneration at the early stage after nerve transection by focusing on the chronological changes in the expression patterns of VEGF-VEGFR signaling. This study used our previously reported experimental model for nerve regeneration following the transection of the inferior alveolar nerve (IAN) in mice. In a double staining of PGP9.5 and CD31, respective markers for the nerve fibers and endothelial cells, CD31 immunoreactions first appeared in the injury site on postoperative (PO) day 2 when the transected nerve fibers had not been re-connected. The most intense immunoreaction for CD31 was found around the regenerating nerve fibers extending from the proximal stump on PO day 3, but it gradually lessened to disappear by PO day 7. The expression patterns of VEGFR1 and VEGFR2 showed similar chronological changes through the observation periods, with most intense immunoreaction found on PO day 3. Western blotting of total protein extracted from the injury site demonstrated the clear bands for VEGF-A and VEGF-B on PO day 2, indicating a time lag for the expression of ligands and receptors. A local administration of antibody to VEGF-A inhibited the elongation of the nerve fibers from the proximal stump. Furthermore, this administration of VEGF-A antibody inhibited the expression of CD31 in the gap between proximal and distal stumps. These results indicated that a nerve injury initiates productions in VEGF-A and VEFG-B, followed with the expression of VEGFR1 and VEGFR2 at early stages after the nerve injury. Taken these findings together, it is reasonable to postulate that immediate response of VEGF-VEGFR signaling to nerve injury plays a crucial role in local angiogenesis, resulting in a trigger for the regeneration of the nerve fibers in mouse IAN.

    DOI: 10.2220/biomedres.39.287

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  • Al-Awadi-Raas-Rothschild syndrome with dental anomalies and a novel WNT7A mutation. 査読 国際誌

    Piranit Nik Kantaputra, Seema Kapoor, Prashant Verma, Massupa Kaewgahya, Katsushige Kawasaki, Atsushi Ohazama, James R Ketudat Cairns

    European journal of medical genetics   60 ( 12 )   695 - 700   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Al-Awadi-Raas-Rothschild syndrome (AARRS; OMIM 276820) is a very rare autosomal recessive limb malformation syndrome caused by WNT7A mutations. AARRS is characterized by various degrees of limb aplasia and hypoplasia. Normal intelligence and malformations of urogenital system are frequent findings. Complete loss of WNT7A function has been shown to cause AARRS, however, its partial loss leads to the milder malformation, Fuhrmann syndrome. An Indian boy affected with AARRS is reported. A novel homozygous base substitution mutation c.550A > C (p.Asn184Asp) is identified in the patient. Parents were heterozygous for the mutation. In addition to the typical features of AARRS, the patient had agenesis of the mandibular left deciduous lateral incisor. The heterozygous parents had microdontia of the maxillary left permanent third molar and taurodontism (enlarged dental pulp chamber at the expense of root) in a number of their permanent molars. Whole exome sequencing of the patient and his parents ruled out mutations in 11 known hypodontia-associated genes including WNT10A, MSX1, EDA, EDAR, EDARADD, PAX9, AXIN2, GREM2, NEMO, KRT17, and TFAP2B. In situ hybridization during tooth development showed Wnt7a expression in wild-type tooth epithelium at E14.5. All lines of evidence suggest that WNT7A has important role in tooth development and its mutation may lead to tooth agenesis, microdontia, and taurodontism. Oral examination of patients with AARRS and Fuhrmann syndromes is highly recommended.

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  • 下顎発生における一次繊毛の機能について

    北村 厚, 川崎 勝盛, 川崎 真依子, 児玉 泰光, 前田 健康, 高木 律男, 大峡 淳

    新潟歯学会雑誌   47 ( 2 )   121 - 122   2017年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 下歯槽神経再生過程へのSemaphorin 3Aの関与について

    金丸 博子, 山田 友里恵, 大峡 淳, 前田 健康, 瀬尾 憲司

    新潟歯学会雑誌   47 ( 2 )   117 - 118   2017年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • The effect of bone mass and architecture on mandibular condyle after mandibular distraction. 査読 国際誌

    Daisuke Suda, Atsushi Ohazama, Takeyasu Maeda, Tadaharu Kobayashi

    Oral surgery, oral medicine, oral pathology and oral radiology   124 ( 4 )   339 - 347   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    OBJECTIVE: Mandibular distraction surgery is a critical treatment for jaw deformity. However, abnormal mandibular condylar bone resorption is often seen as complication after surgery. Our previous study using a rat mandibular distraction model suggested that overloading leads to mandibular condylar resorption. Host factors are also believed to influence the resorption. To understand the relationship between host factors and resorption, we investigated the effect of changing bone mass and architecture on the mandibular condyle using FK506. STUDY DESIGN: FK506, an immunosuppressant, was used to compromise bone mass and architecture in this study. Animals were divided into 4 groups: distraction surgery (Dist), FK506 administration (FK), distraction surgery with FK506 administration (FK + Dist), and no surgery or FK506 administration (Cont). RESULTS: The FK group showed reduced bone mass and impaired bone architecture. The Dist group exhibited abnormal bone resorption on the surface of the condyles, which was slightly exacerbated in the FK + Dist group. Bone defect length decreased over time as a result of bone apposition in the Dist group. However, in the FK + Dist group, the bone defect length remained the same. CONCLUSIONS: These results suggest that bone mass and architecture strongly affect the tolerance to the overloading and adaptation with bone apposition in condylar resorption site.

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  • A novel GJA1 mutation in oculodentodigital dysplasia with extensive loss of enamel 査読

    T. Porntaveetus, C. Srichomthong, A. Ohazama, K. Suphapeetiporn, V. Shotelersuk

    ORAL DISEASES   23 ( 6 )   795 - 800   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Objective: To characterize clinical features and identify genetic causes of a patient with oculodentodigital dysplasia (ODDD).
    Subjects and methods: Clinical, dental, radiological features were obtained. DNA was collected from an affected Thai family. Whole-exome sequencing was employed to identify the disease-causing mutation causing ODDD. The presence of the identified variant was confirmed by Sanger sequencing.
    Results: The proband suffered with extensive enamel hypoplasia, polysyndactyly and clinodactyly of the 3rd-5th fingers, microphthalmia, and unique facial characteristics of ODDD. Mutation analysis revealed a novel missense mutation, c. 31C&gt;A, p.L11I, in the GJA1 gene which encodes gap junction channel protein connexin 43. Bioinformatics and structural modeling suggested the mutation to be pathogenic. The parents did not harbor the mutation.
    Conclusions: This study identified a novel de novo mutation in the GJA1 gene associated with severe tooth defects. These results expand the mutation spectrum and understanding of pathologic dental phenotypes related to ODDD.

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  • TFAP2B mutation and dental anomalies. 査読 国際誌

    Natchaya Tanasubsinn, Rekwan Sittiwangkul, Yupada Pongprot, Katsushige Kawasaki, Atsushi Ohazama, Thanapat Sastraruji, Massupa Kaewgahya, Piranit Nik Kantaputra

    Journal of human genetics   62 ( 8 )   769 - 775   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Mutations inTFAP2B has been reported in patients with isolated patent ductus arteriosus (PDA) and Char syndrome. We performed mutation analysis of TFAP2B in 43 patients with isolated PDA, 7 patients with PDA with other congenital heart defects and 286 patients with isolated tooth agenesis with or without other dental anomalies. The heterozygous c.1006G>A mutation was identified in 20 individuals. Those mutation carriers consisted of 1 patient with term PDA (1/43), 16 patients with isolated tooth agenesis with or without other dental anomalies (16/286; 5.6%), 1 patient with PDA and severe valvular aortic stenosis and tooth agenesis (1/4) and 2 normal controls (2/100; 1%). The mutation is predicted to cause an amino-acid substitution p.Val336Ile in the TFAP2B protein. Tfap2b expression during early mouse tooth development supports the association of TFAP2B mutation and dental anomalies. It is hypothesized that this incidence might have been the result of founder effect. Here we report for the first time that TFAP2B mutation is associated with tooth agenesis, microdontia, supernumerary tooth and root maldevelopment. In addition, we also found that TFAP2B mutations, the common causes of PDA in Caucasian, are not the common cause of PDA in Thai population.

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  • 下歯槽神経再生におけるSonic Hedgehogシグナルの機能に関する検討

    山田 友里恵, 大峡 淳, 前田 健康, 瀬尾 憲司

    新潟歯学会雑誌   46 ( 2 )   108 - 108   2016年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Ofd1は口蓋突起の下方伸長に必須である

    渡部 桃子, 川崎 勝盛, 川崎 真依子, 永井 孝宏, 北村 厚, 児玉 泰光, 前田 健康, 高木 律男, 大峡 淳

    新潟歯学会雑誌   46 ( 2 )   108 - 109   2016年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • 間葉のMicroRNAは、眼瞼発生を制御する

    永井 孝宏, 渡部 桃子, 川崎 真依子, 川崎 勝盛, 北村 厚, 児玉 泰光, 高木 律男, 前田 健康, 大峡 淳

    新潟歯学会雑誌   46 ( 2 )   114 - 115   2016年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • ラット下顎骨延長モデルにおける下顎頭吸収と骨質の関連性について

    須田 大亮, 大峡 淳, 前田 健康

    新潟歯学会雑誌   46 ( 2 )   109 - 109   2016年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • Regional Regulation of Filiform Tongue Papillae Development by Ikk alpha/Irf6 査読

    Maiko Kawasaki, Katsushige Kawasaki, Shelly Oommen, James Blackburn, Momoko Watanabe, Takahiro Nagai, Atsushi Kitamura, Takeyasu Maeda, Bigang Liu, Ruth Schmidt-Ullrich, Taishin Akiyama, Jun-Ichiro Inoue, Nigel L. Hammond, Paul T. Sharpe, Atsushi Ohazama

    DEVELOPMENTAL DYNAMICS   245 ( 9 )   937 - 946   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background: Non-gustatory filiform papillae play critical roles in helping to grip food, drawing food to the esophagus, cleaning the mouth, and spreading saliva. The molecular mechanisms of filiform tongue papillae development however are not fully understood. Results: We found Ikk alpha and Irf6 expression in developing tongue epithelium, and describe here specific tongue abnormalities in mice with mutation of these genes, indicating a role for Ikk alpha and Irf6 in filiform papillae development. Ikk alpha and Irf6 mutant tongues showed ectopic vertical epithelium at the midline, while lateral sides of mutant tongues adhered to the oral mucosa. Both the ectopic median vertical epithelium and adhered epithelium exhibited the presence of filiform tongue papillae, whereas epithelium between the median vertical epithelium and adhered tongue showed a loss of filiform tongue papillae. Timing of filiform papillae development was found to be slightly different between the midline and lateral regions of the wild-type tongue. Conclusions: Filiform papillae thus develop through distinct molecular mechanisms between the regions of tongue dorsum in the medio-lateral axis, with some filiform papillae developing under the control of Ikk alpha and Irf6. Developmental Dynamics 245: 937-946, 2016. (C) 2016 Wiley Periodicals, Inc.

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  • Spatio-temporal expression of Sox genes in murine palatogenesis 査読

    Momoko Watanabe, Katsushige Kawasaki, Maiko Kawasaki, Thantrira Portaveetus, Shelly Oommen, James Blackburn, Takahiro Nagai, Atsushi Kitamura, Atsushi Nishikawa, Yasumitsu Kodama, Ritsuo Takagi, Takeyasu Maeda, Paul T. Sharpe, Atsushi Ohazama

    GENE EXPRESSION PATTERNS   21 ( 2 )   111 - 118   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Members of the Sox gene family play critical roles in many biological processes including organogenesis. We carried out comparative in situ hybridisation analysis of seventeen Sox genes (Sox1-14, 17, 18 and 21) during murine palatogenesis from initiation to fusion of the palatal shelves above the dorsal side of the tongue. At palatal shelf initiation (E12.5), the localized expression of six Sox genes (Sox2, 5, 6, 9,12 and 13) was observed in the shelves, whereas Sox4 and Sox11 showed ubiquitious expression. During the down growth of palatal shelves (E13.5), Sox4, Sox5, and Sox9 exhibited restricted expression to the interior side of the palatal shelves facing the tongue. Following elevation of the palatal shelves (E14.5), Sox2, Sox11 and Sox21 expression was present in the midline epithelial seam. We thus identify dynamic spatio-temporal expression of Sox gene family during the process of palatogenesis. (C) 2016 Elsevier B.V. All rights reserved.

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  • Disrupted mitochondrial function in the Opa3(L122P) mouse model for Costeff Syndrome impairs skeletal integrity 査読

    Alice E. Navein, Esther J. Cooke, Jennifer R. Davies, Terence G. Smith, Lois H. M. Wells, Atsushi Ohazama, Christopher Healy, Paul T. Sharpe, Sam L. Evans, Bronwen A. J. Evans, Marcela Votruba, Timothy Wells

    HUMAN MOLECULAR GENETICS   25 ( 12 )   2404 - 2416   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Mitochondrial dysfunction connects metabolic disturbance with numerous pathologies, but the significance of mitochondrial activity in bone remains unclear. We have, therefore, characterized the skeletal phenotype in the Opa3(L122P) mouse model for Costeff syndrome, in which a missense mutation of the mitochondrial membrane protein, Opa3, impairs mitochondrial activity resulting in visual and metabolic dysfunction. Although widely expressed in the developing normal mouse head, Opa3 expression was restricted after E14.5 to the retina, brain, teeth and mandibular bone. Opa3 was also expressed in adult tibiae, including at the trabecular surfaces and in cortical osteocytes, epiphyseal chondrocytes, marrow adipocytes and mesenchymal stem cell rosettes. Opa3(L122P) mice displayed craniofacial abnormalities, including undergrowth of the lower mandible, accompanied in some individuals by cranial asymmetry and incisor malocclusion. Opa3(L122P) mice showed an 8-fold elevation in tibial marrow adiposity, due largely to increased adipogenesis. In addition, femoral length and cortical diameter and wall thickness were reduced, the weakening of the calcified tissue and the geometric component of strength reducing overall cortical strength in Opa3(L122P) mice by 65%. In lumbar vertebrae reduced vertebral body area and wall thickness were accompanied by a proportionate reduction in marrow adiposity. Although the total biomechanical strength of lumbar vertebrae was reduced by 35%, the strength of the calcified tissue (sigma(max)) was proportionate to a 38% increase in trabecular number. Thus, mitochondrial function is important for the development and maintenance of skeletal integrity, impaired bone growth and strength, particularly in limb bones, representing a significant new feature of the Costeff syndrome phenotype.

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  • Contribution of synovial lining cells to synovial vascularization of the rat temporomandibular joint 査読

    Kayoko Nozawa-Inoue, Fumiko Harada, Jin Magara, Atsushi Ohazama, Takeyasu Maeda

    JOURNAL OF ANATOMY   228 ( 3 )   520 - 529   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The lining layer of the synovial membrane in the temporomandibular joint (TMJ) contains two types of lining cells: macrophage-like type A and fibroblast-like type B cells. The type B cells are particularly heterogeneous in their morphology and immunoreactivity, so that details of their functions remain unclear. Some of the type B cells exhibit certain resemblances in their ultrastructure to those of an activated capillary pericyte at the initial stage of the angiogenesis. The articular surface, composed of cartilage and the disc in the TMJ, has few vasculatures, whereas the synovial lining layer is richly equipped with blood capillaries to produce the constituent of synovial fluid. The present study investigated at both the light and electron microscopic levels the immunocytochemical characteristics of the synovial lining cells in the adult rat TMJ, focusing on their contribution to the synovial vascularization. It also employed an intravascular perfusion with Lycopersicon esculentum (tomato) lectin to identify functional vessels in vivo. Results showed that several type B cells expressed desmin, a muscle-specific intermediate filament which is known as the earliest protein to appear during myogenesis as well as being a marker for the immature capillary pericyte. These desmin-positive type B cells showed immunoreactions for vimentin and pericyte markers (neuron-glial 2; NG2 and PDGFRb) but not for the other markers of myogenic cells (MyoD and myogenin) or a contractile apparatus (aSMA and caldesmon). Immunoreactivity for RECA-1, an endothelial marker, was observed in the macrophage-like type A cells. The arterioles and venules inside the synovial folds extended numerous capillaries with RECA-1-positive endothelial cells and desmin-positive pericytes to distribute densely in the lining layer. The distal portion of these capillaries showing RECA-1-immunoreactivity lacked lectin-staining, indicating a loss of blood-circulation due to sprouting or termination in the lining layer. The desmin-positive type B and RECA-1-positive type A cells attached to this portion of the capillaries. Some capillaries in the lining layer also expressed ninein, a marker for sprouting endothelial cells, called tip cells. Since an activated pericyte, macrophage and tip cell are known to act together at the forefront of the vessel sprout during angiogenesis, the desmin-positive type B cell and RECA-1-positive type A cell might serve as these angiogenic cells in the synovial lining layer. Tomato lectin perfusion following decalcification would be a highly useful tool for research on the vasculature of the mineralized tissue. Use of this technique combined with immunohistochemistry should permit future extensive investigations on the presence of the physiological angiogenesis and on the function of the lining cells in the synovial membrane. Key words: angiogenesis; synovial lining cell; synovial membrane; temporomandibular joint; tomato lectin.

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  • GREMLIN 2 Mutations and Dental Anomalies 査読

    P. N. Kantaputra, M. Kaewgahya, A. Hatsadaloi, P. Vogel, K. Kawasaki, A. Ohazama, J. R. Ketudat Cairns

    JOURNAL OF DENTAL RESEARCH   94 ( 12 )   1646 - 1652   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE PUBLICATIONS INC  

    Isolated or nonsyndromic tooth agenesis or hypodontia is the most common human malformation. It has been associated with mutations in MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, and WNT10A. GREMLIN 2 (GREM2) is a strong bone morphogenetic protein (BMP) antagonist that is known to regulate BMPs in embryogenesis and tissue development. Bmp4 has been shown to have a role in tooth development. Grem2(-/-) mice have small, malformed maxillary and mandibular incisors, indicating that Grem2 has important roles in normal tooth development. Here, we demonstrate for the first time that GREM2 mutations are associated with human malformations, which include isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow-growing hair, and dry and itchy skin. We sequenced WNT10A, WNT10B, MSX1, EDA, EDAR, EDARADD, AXIN2, and PAX9 in all 7 patients to rule out the effects of other ectodermal dysplasias and other tooth-related genes and did not find mutations in any of them. GREM2 mutations exhibit variable expressivity even within the same families. The inheritance is autosomal dominant with incomplete penetrance. The expression of Grem2 during the early development of mouse teeth and hair follicles and the evaluation of the likely effects of the mutations on the protein structure substantiate these new findings.

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  • Craniofacial Development and Growth in Polycystic Kidney Disease 査読

    Atsushi Ohazama, Paul T. Sharpe

    2015年11月

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    記述言語:英語   出版者・発行元:Codon Publications  

    Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the presence of multiple cysts in kidneys. ADPKD has been shown to be caused by mutations in the genes of PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins are localized in primary cilia that play roles in multiple biological processes including mechanoreception, Ca2+ influx and cell signalling pathways. Primary cilia are known to play important roles in regulating craniofacial development and growth. In this chapter, we summarize the function of Pkd1 and Pkd2 in controlling mouse craniofacial development and growth, and discuss PKD-associated molecular mechanisms.

    DOI: 10.15586/codon.pkd.2015

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  • 口蓋発生におけるOfd1の役割について

    渡部 桃子, 川崎 真依子, 高木 律男, 前田 健康, 大峡 淳

    Journal of Oral Biosciences Supplement   2015   240 - 240   2015年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • Excess NF-κB induces ectopic odontogenesis in embryonic incisor epithelium 査読

    Blackburn J, Kawasaki K, Porntaveetus T, Kawasaki M, Otsuka-Tanaka Y, Miake Y, Ota MS, Watanabe M, Hishinuma M, Nomoto T, Oommen S, Ghafoor S, Harada F, Nozawa-Inoue K, Maeda T, Peterkov_ R, Lesot H, Inoue J, Akiyama T, Schmidt-Ullrich R, Liu B, Hu Y, Page A, Ram_rez A, Sharpe PT, Ohazama A

    Journal of Dental Research   94 ( 1 )   121 - 128   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1177/0022034514556707

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  • Expression of Sox genes in tooth development 査読

    Katsushige Kawasaki, Maiko Kawasaki, Momoko Watanabe, Erik Idrus, Takahiro Nagai, Shelly Oommen, Takeyasu Maeda, Nobuko Hagiwara, Jianwen Que, Paul T. Sharpe, Atsushi Ohazama

    INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY   59 ( 10-12 )   471 - 478   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:UNIV BASQUE COUNTRY UPV-EHU PRESS  

    Members of the Sox gene family play roles in many biological processes including organogenesis. We carried out comparative in situ hybridization analysis of seventeen sox genes (Sox 1-14, 17, 18, 21) during murine odontogenesis from the epithelial thickening to the cytodifferentiation stages. Localized expression of five Sox genes (Sox6, 9, 13, 14 and 21) was observed in tooth bud epithelium. Sox13 showed restricted expression in the primary enamel knots. At the early bell stage, three Sox genes (Sox8, 11, 17 and 21) were expressed in pre-ameloblasts, whereas two others (Sox5 and 18) showed expression in odontoblasts. Sox genes thus showed a dynamic spatio-temporal expression during tooth development.

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  • Root dentin anomaly and a PLG mutation 査読

    Napaporn Tananuvat, Pimlak Charoenkwan, Atsushi Ohazama, James R. Ketuda Cairns, Massupa Kaewgahya, Piranit Nik Kantaputra

    EUROPEAN JOURNAL OF MEDICAL GENETICS   57 ( 11-12 )   630 - 635   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We report a Thai girl affected with plasminogen deficiency, Type I. Ligneous conjunctivitis was first observed when she was one-month-old. The newly recognized findings include tapered incisor roots as a result of thin root dentin, generalized short tooth roots, and mandibular prognathism. Mutation analysis of PLG demonstrated homozygous c.1193G&gt;A missense mutation. The parents were heterozygous for c.1193G&gt;A mutation. The c.1193G&gt;A mutation is novel and predicted to cause amino acid substitution p.Cys398Tyr. Thin root dentin in the patient who was affected with PLG mutation and immunolocalization of Plg during early root development in mice imply the role of plasminogen in root dentin formation. (C) 2014 Elsevier Masson SAS. All rights reserved.

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  • Submicron Imaging of Soft-Tissues Using Low-Dose Phase-Contrast X-Ray Synchrotron Microtomography with an Iodine Contrast Agent 査読

    R. H. Khonsari, C. Healy, A. Ohazama, P. T. Sharpe, R. H. Khonsari, H. Dutel, H. Dutel, C. Charles, L. Viriot, P. Tafforeau

    ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY   297 ( 10 )   1803 - 1807   2014年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    DOI: 10.1002/ar.22997

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  • ラット顎関節滑膜におけるデスミン免疫陽性B型およびRECA-1免疫陽性A型表層細胞の血管形成への関与

    野澤 佳世子[井上], 真柄 仁, 河野 芳朗, 大峡 淳, 前田 健康

    Journal of Oral Biosciences Supplement   2014   193 - 193   2014年9月

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    記述言語:日本語   出版者・発行元:(一社)歯科基礎医学会  

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  • Enamel-Renal-Gingival Syndrome, Hypodontia, and a Novel FAM20A Mutation 査読

    Piranit Nik Kantaputra, Chotika Bongkochwilawan, Massupa Kaewgahya, Atsushi Ohazama, Hulya Kayserili, Arzu Pinar Erdem, Oya Aktoren, Yeliz Guven

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   164 ( 8 )   2124 - 2128   2014年8月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    DOI: 10.1002/ajmg.a.36579

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  • R-spondins/Lgrs expression in tooth development 査読

    Maiko Kawasaki, Thantrira Porntaveetus, Katsushige Kawasaki, Shelly Oommen, Yoko Otsuka-Tanaka, Mitsue Hishinuma, Takato Nomoto, Takeyasu Maeda, Keiyo Takubo, Toshio Suda, Paul T. Sharpe, Atsushi Ohazama

    DEVELOPMENTAL DYNAMICS   243 ( 6 )   844 - 851   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background: Tooth development is highly regulated in mammals and it is regulated by networks of signaling pathways (e. g. Tnf, Wnt, Shh, Fgf and Bmp) whose activities are controlled by the balance between ligands, activators, inhibitors and receptors. The members of the R-spondin family are known as activators of Wnt signaling, and Lgr4, Lgr5, and Lgr6 have been identified as receptors for R-spondins. The role of R-spondin/Lgr signaling in tooth development, however, remains unclear. Results: We first carried out comparative in situ hybridization analysis of R-spondins and Lgrs, and identified their dynamic spatio-temporal expression in murine odontogenesis. R-spondin2 expression was found both in tooth germs and the tooth-less region, the diastema. We further examined tooth development in R-spondin2 mutant mice, and although molars and incisors exhibited no significant abnormalities, supernumerary teeth were observed in the diastema. Conclusions: R-spondin/Lgr signaling is thus involved in tooth development. Developmental Dynamics 243:844-851, 2014. (c) 2014 Wiley Periodicals, Inc.

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  • PKA regulatory subunit expression in tooth development 査読

    Silvia Ferreira de Sousa, Katsushige Kawasaki, Maiko Kawasaki, Ana Angelova Volponi, Ricardo Santiago Gomez, Carolina Cavalieri Gomes, Paul T. Sharpe, Atsushi Ohazama

    GENE EXPRESSION PATTERNS   15 ( 1 )   46 - 51   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Protein kinase A (PK A) plays critical roles in many biological processes including cell proliferation, cell differentiation, cellular metabolism and gene regulation. Mutation in PKA regulatory subunit, PRKAR1A has previously been identified in odontogenic myxomas, but it is unclear whether PKA is involved in tooth development. The aim of the present study was to assess the expression of alpha isoforms of PICA regulatory subunit (Prkar1a and Prkar2a) in mouse and human odontogenesis by in situ hybridization. PRKAR1A and PRKAR2A mRNA transcription was further confirmed in a human deciduous germ by qRT-PCR. Mouse Prkar1a and human PRKAR2A exhibited a dynamic spatio-temporal expression in tooth development, whereas neither human PRKAR1A nor mouse Prkar2a showed their expression in odontogenesis. These isoforms thus showed different expression pattern between human and mouse tooth germs. (C) 2014 Elsevier B.V. All rights reserved.

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  • Shape and Volume of Craniofacial Cavities in Intentional Skull Deformations 査読

    R. H. Khonsari, M. Friess, J. Nysjo, G. Odri, F. Malmberg, I. Nystrom, E. Messo, J. M. Hirsch, E. A. M. Cabanis, K. H. Kunzelmann, J. M. Salagnac, P. Corre, A. Ohazama, P. T. Sharpe, P. Charlier, R. Olszewski

    AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY   151 ( 1 )   110 - 119   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Intentional cranial deformations (ICD) have been observed worldwide but are especially prevalent in preColombian cultures. The purpose of this study was to assess the consequences of ICD on three cranial cavities (intracranial cavity, orbits, and maxillary sinuses) and on cranial vault thickness, in order to screen for morphological changes due to the external constraints exerted by the deformation device. We acquired CT-scans for 39 deformed and 19 control skulls. We studied the thickness of the skull vault using qualitative and quantitative methods. We computed the volumes of the orbits, of the maxillary sinuses, and of the intracranial cavity using haptic-aided semi-automatic segmentation. We finally defined 3D distances and angles within orbits and maxillary sinuses based on 27 anatomical landmarks and measured these features on the 58 skulls. Our results show specific bone thickness patterns in some types of ICD, with localized thinning in regions subjected to increased pressure and thickening in other regions. Our findings confirm that volumes of the cranial cavities are not affected by ICDs but that the shapes of the orbits and of the maxillary sinuses are modified in circumferential deformations. We conclude that ICDs can modify the shape of the cranial cavities and the thickness of their walls but conserve their volumes. These results provide new insights into the morphological effects associated with ICDs and call for similar investigations in subjects with deformational plagiocephalies and craniosynostoses. Am J Phys Anthropol 151:110-119, 2013. (C) 2013 Wiley Periodicals, Inc.

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  • A mathematical model for mechanotransduction at the early steps of suture formation 査読

    R. H. Khonsari, J. Olivier, P. Vigneaux, S. Sanchez, P. Tafforeau, P. E. Ahlberg, F. Di Rocco, D. Bresch, P. Corre, A. Ohazama, P. T. Sharpe, V. Calvez

    PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES   280 ( 1759 )   20122670   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ROYAL SOC  

    Growth and patterning of craniofacial sutures is subjected to the effects of mechanical stress. Mechanotransduction processes occurring at the margins of the sutures are not precisely understood. Here, we propose a simple theoretical model based on the orientation of collagen fibres within the suture in response to local stress. We demonstrate that fibre alignment generates an instability leading to the emergence of interdigitations. We confirm the appearance of this instability both analytically and numerically. To support our model, we use histology and synchrotron X-ray microtomography and reveal the fine structure of fibres within the sutural mesenchyme and their insertion into the bone. Furthermore, using a mouse model with impaired mechanotransduction, we show that the architecture of sutures is disturbed when forces are not interpreted properly. Finally, by studying the structure of sutures in the mouse, the rat, an actinopterygian (Polypterus bichir) and a placoderm(Compagopiscis croucheri), we show that bone deposition patterns during dermal bone growth are conserved within jawed vertebrates. In total, these results support the role of mechanical constraints in the growth and patterning of craniofacial sutures, a process that was probably effective at the emergence of gnathostomes, and provide new directions for the understanding of normal and pathological suture fusion.

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  • Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2) 査読

    Roman H. Khonsari, Atsushi Ohazama, Ramin Raouf, Maiko Kawasaki, Katsushige Kawasaki, Thantrira Porntaveetus, Sarah Ghafoor, Peter Hammond, Michael Suttie, Guillaume A. Odri, Richard N. Sandford, John N. Wood, Paul T. Sharpe

    HUMAN MOLECULAR GENETICS   22 ( 9 )   1873 - 1885   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Polycystin 2 (Pkd2), which belongs to the transient receptor potential family, plays a critical role in development. Pkd2 is mainly localized in the primary cilia, which also function as mechanoreceptors in many cells that influence multiple biological processes including Ca-2 influx, chemical activity and signalling pathways. Mutations in many cilia proteins result in craniofacial abnormalities. Orofacial tissues constantly receive mechanical forces and are known to develop and grow through intricate signalling pathways. Here we investigate the role of Pkd2, whose role remains unclear in craniofacial development and growth. In order to determine the role of Pkd2 in craniofacial development, we located expression in craniofacial tissues and analysed mice with conditional deletion of Pkd2 in neural crest-derived cells, using Wnt1Cre mice. Pkd2 mutants showed many signs of mechanical trauma such as fractured molar roots, distorted incisors, alveolar bone loss and compressed temporomandibular joints, in addition to abnormal skull shapes. Significantly, mutants showed no indication of any of these phenotypes at embryonic stages when heads perceive no significant mechanical stress in utero. The results suggest that Pkd2 is likely to play a critical role in craniofacial growth as a mechanoreceptor. Pkd2 is also identified as one of the genes responsible for autosomal dominant polycystic kidney disease (ADPKD). Since facial anomalies have never been identified in ADPKD patients, we carried out three-dimensional photography of patient faces and analysed these using dense surface modelling. This analysis revealed specific characteristics of ADPKD patient faces, some of which correlated with those of the mutant mice.

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  • The buccohypophyseal canal is an ancestral vertebrate trait maintained by modulation in sonic hedgehog signaling 査読

    Roman H. Khonsari, Maisa Seppala, Alan Pradel, Hugo Dutel, Gael Clement, Oleg Lebedev, Sarah Ghafoor, Michaela Rothova, Abigael Tucker, John G. Maisey, Chen-Ming Fan, Maiko Kawasaki, Atsushi Ohazama, Paul Tafforeau, Brunella Franco, Jill Helms, Courtney J. Haycraft, Albert David, Philippe Janvier, Martyn T. Cobourne, Paul T. Sharpe

    BMC BIOLOGY   11   27   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: The pituitary gland is formed by the juxtaposition of two tissues: neuroectoderm arising from the basal diencephalon, and oral epithelium, which invaginates towards the central nervous system from the roof of the mouth. The oral invagination that reaches the brain from the mouth is referred to as Rathke's pouch, with the tip forming the adenohypophysis and the stalk disappearing after the earliest stages of development. In tetrapods, formation of the cranial base establishes a definitive barrier between the pituitary and oral cavity; however, numerous extinct and extant vertebrate species retain an open buccohypophyseal canal in adulthood, a vestige of the stalk of Rathke's pouch. Little is currently known about the formation and function of this structure. Here we have investigated molecular mechanisms driving the formation of the buccohypophyseal canal and their evolutionary significance.
    Results: We show that Rathke's pouch is located at a boundary region delineated by endoderm, neural crest-derived oral mesenchyme and the anterior limit of the notochord, using CD1, R26R-Sox17-Cre and R26R-Wnt1-Cre mouse lines. As revealed by synchrotron X-ray microtomography after iodine staining in mouse embryos, the pouch has a lobulated three-dimensional structure that embraces the descending diencephalon during pituitary formation. Polaris(fl/fl); Wnt1-Cre, Ofd1(-/-) and Kif3a(-/-) primary cilia mouse mutants have abnormal sonic hedgehog (Shh) signaling and all present with malformations of the anterior pituitary gland and midline structures of the anterior cranial base. Changes in the expressions of Shh downstream genes are confirmed in Gas1(-/-) mice. From an evolutionary perspective, persistence of the buccohypophyseal canal is a basal character for all vertebrates and its maintenance in several groups is related to a specific morphology of the midline that can be related to modulation in Shh signaling.
    Conclusion: These results provide insight into a poorly understood ancestral vertebrate structure. It appears that the opening of the buccohypophyseal canal depends upon Shh signaling and that modulation in this pathway most probably accounts for its persistence in phylogeny.

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  • Oral lining mucosa development depends on mesenchymal microRNAs 査読

    Y. Otsuka-Tanaka, S. Oommen, M. Kawasaki, K. Kawasaki, N. Imam, F. Jalani-Ghazani, R. Hindges, P. T. Sharpe, A. Ohazama

    Journal of Dental Research   92 ( 3 )   229 - 234   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The oral mucosa plays critical roles in protection, sensation, and secretion and can be classified into masticatory, lining, and specialized mucosa that are known to be functionally, histologically, and clinically distinct. Each type of oral mucosa is believed to develop through discrete molecular mechanisms, which remain unclear. MicroRNAs (miRNAs) are 19 to 25nt non-coding small single-stranded RNAs that negatively regulate gene expression by binding target mRNAs. miRNAs are crucial for fine-tuning of molecular mechanisms. To investigate the role of miRNAs in oral mucosa development, we examined mice with mesenchymal (Wnt1Cre
    Dicerfl/fl) conditional deletion of Dicer. Wnt1Cre
    Dicerfl/fl mice showed trans-differentiation of lining mucosa into an epithelium with masticatory mucosa/ skin-specific characteristics. Up-regulation of Fgf signaling was found in mutant lining mucosal epithelium that was accompanied by an increase in Fgf7 expression in mutant mesenchyme. Mesenchyme miRNAs thus have an indirect effect on lining mucosal epithelial cell growth/differentiation. © International &amp
    American Associations for Dental Research 2013.

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  • The origin of the stapes and relationship to the otic capsule and oval window 査読

    Hannah Thompson, Atsushi Ohazama, Paul T. Sharpe, Abigail S. Tucker

    DEVELOPMENTAL DYNAMICS   241 ( 9 )   1396 - +   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background: The stapes, an ossicle found within the middle ear, is involved in transmitting sound waves to the inner ear by means of the oval window. There are several developmental problems associated with this ossicle and the oval window, which cause hearing loss. The developmental origin of these tissues has not been fully elucidated. Results: Using transgenic reporter mice, we have shown that the stapes is of dual origin with the stapedial footplate being composed of cells of both neural crest and mesodermal origin. Wnt1cre/Dicer mice fail to develop neural crest-derived cartilages, therefore, have no middle ear ossicles. We have shown in these mice the mesodermal stapedial footplate fails to form and the oval window is induced but underdeveloped. Conclusions: If the neural crest part of the stapes fails to form the mesodermal part does not develop, indicating that the two parts are interdependent. The stapes develops tightly associated with the otic capsule, however, it is not essential for the positioning of the oval window, suggesting that other tissues, perhaps within the inner ear are needed for oval window placement. Developmental Dynamics 241:1396-1404, 2012. (c) 2012 Wiley Periodicals, Inc.

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  • Dyschromatosis Symmetrica Hereditaria With Long Hair on the Forearms, Hypo/Hyperpigmented Hair, and Dental Anomalies: Report of a Novel ADAR1 Mutation 査読

    Piranit Nik Kantaputra, Wannapa Chinadet, Atsushi Ohazama, Michihiro Kono

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 9 )   2258 - 2265   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We report on a father and his two children who are affected with dyschromatosis symmetrica hereditaria (DSH). Mutation analysis of ADAR1 gene demonstrated a novel splice acceptor site mutation in intron 10, IVS10-2A&gt;C. The hair on the forearm of the affected father became longer, larger in diameter, and hypopigmented (white) after age 40 years. Hyperpigmented hair was also found in normal and hypopigmented skin. The colors of the hair and the skin did not correlate. Transmission electron micrography of cortical keratinocytes of the hair follicles showed that normal hair contained more keratinocytes than those of hyperpigmented and hypopigmented hair. The keratinocytes of the hyperpigmented hair were larger than those of normal and hypopigmented hair and those of the normal hair were larger than those of the hypopigmented hair. The affected daughter had dens evaginatus of the mandibular right second premolar and the son had dens invaginatus of the maxillary permanent lateral incisors. Expression of Adar1 gene during mouse tooth development is demonstrated. (C) 2012 Wiley Periodicals, Inc.

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  • Cytoplasmic Plaque Formation in Hemidesmosome Development Is Dependent on SoxF Transcription Factor Function 査読

    Shelly Oommen, Mathias Francois, Maiko Kawasaki, Melanie Murrell, Katsushige Kawasaki, Thantrira Porntaveetus, Sarah Ghafoor, Neville J. Young, Yoshimasa Okamatsu, John McGrath, Peter Koopman, Paul T. Sharpe, Atsushi Ohazama

    PLOS ONE   7 ( 9 )   e43857   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Hemidesmosomes are composed of intricate networks of proteins, that are an essential attachment apparatus for the integrity of epithelial tissue. Disruption leads to blistering diseases such as epidermolysis bullosa. Members of the Sox gene family show dynamic and diverse expression patterns during development and mutation analyses in humans and mice provide evidence that they play a remarkable variety of roles in development and human disease. Previous studies have established that the mouse mutant ragged-opossum (Ra-op) expresses a dominant-negative form of the SOX18 transcription factor that interferes with the function of wild type SOX18 and of the related SOXF-subgroup proteins SOX7 and -17. Here we show that skin and oral mucosa in homozygous Ra-op mice display extensive detachment of epithelium from the underlying mesenchymal tissue, caused by tearing of epithelial cells just above the plasma membrane due to hemidesmosome disruption. In addition, several hemidesmosome proteins expression were found to be dysregulated in the Ra-op mice. Our data suggest that SOXF transcription factors play a role in regulating formation of cytoplasmic plaque protein assembly, and that disrupted SOXF function results in epidermolysis bullosa-like skin phenotypes.

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  • Distinct roles of MicroRNAs in epithelium and mesenchyme during tooth development 査読

    Shelly Oommen, Yoko Otsuka-Tanaka, Najam Imam, Maiko Kawasaki, Katsushige Kawasaki, Farnoosh Jalani-Ghazani, Angela Anderegg, Rajeshwar Awatramani, Robert Hindges, Paul T. Sharpe, Atsushi Ohazama

    DEVELOPMENTAL DYNAMICS   241 ( 9 )   1465 - 1472   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Background: Tooth development is known to be mediated by the cross-talk between signaling pathways, including Shh, Fgf, Bmp, and Wnt. MicroRNAs (miRNAs) are 19- to 25-nt noncoding small single-stranded RNAs that negatively regulate gene expression by binding target mRNAs, which is believed to be important for the fine-tuning signaling pathways in development. To investigate the role of miRNAs in tooth development, we examined mice with either mesenchymal (Wnt1Cre/Dicerfl/fl) or epithelial (ShhCre/Dicerfl/fl) conditional deletion of Dicer, which is essential for miRNA processing. Results: By using a CD1 genetic background for Wnt1Cre/Dicerfl/fl, we were able to examine tooth development, because the mutants retained mandible and maxilla primordia. Wnt1Cre/Dicerfl/fl mice showed an arrest or absence of teeth development, which varied in frequency between incisors and molars. Extra incisor tooth formation was found in ShhCre/Dicerfl/fl mice, whereas molars showed no significant anomalies. Microarray and in situ hybridization analysis identified several miRNAs that showed differential expression between incisors and molars. Conclusion: In tooth development, miRNAs thus play different roles in epithelium and mesenchyme, and in incisors and molars. Developmental Dynamics 241:1465-1472, 2012. (c) 2012 Wiley Periodicals, Inc.

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  • Wnt signaling in the murine diastema 査読

    Thantrira Porntaveetus, Atsushi Ohazama, Hong Y. Choi, Joachim Herz, Paul T. Sharpe

    EUROPEAN JOURNAL OF ORTHODONTICS   34 ( 4 )   518 - 524   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    The correct number and shape of teeth are critical factors for an aesthetic and functional dentition. Understanding the molecular mechanisms regulating tooth number and shape are therefore important in orthodontics. Mice have only one incisor and three molars in each jaw quadrant that are divided by a tooth-less region, the diastema. Although mice lost teeth in the diastema during evolution, the remnants of the evolutionary lost teeth are observed as transient epithelial buds in the wild-type diastema during early stages of development. Shh and Fgf signaling pathways that are essential for tooth development have been shown to be repressed in the diastema. It remains unclear however how Wnt signaling, that is also required for tooth development, is regulated in the diastema. In this study we found that in the embryonic diastema, Wnt5a expression was observed in mesenchyme, whereas Wnt4 and Wnt10b were expressed in epithelium. The expression of Wnt6 and Wnt11 was found in both tissues. The Wnt co-receptor, Lrp6, was weakly expressed in the diastema overlapping with weak Lrp4 expression, a co-receptor that inhibits Wnt signaling. Secreted Wnt inihibitors Dkk1, Dkk2, and Dkk3 were also expressed in the diastema. Lrp4 mutant mice develop supernumerary teeth in the diastema that is accompanied by upregulation of Wnt signaling and Lrp6 expression. Wnt signaling is thus usually attenuated in the diastema by these secreted and membrane bound Wnt inhibitors.

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  • Bmp signalling in filiform tongue papillae development 査読

    Katsushige Kawasaki, Thantrira Porntaveetus, Shelly Oommen, Sarah Ghafoor, Maiko Kawasaki, Yoko Otsuka-Tanaka, James Blackburn, John A. Kessler, Paul T. Sharpe, Atsushi Ohazama

    ARCHIVES OF ORAL BIOLOGY   57 ( 6 )   805 - 813   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Objective: Tongue papillae are critical organs in mastication. There are four different types of tongue papillae; fungiform, circumvallate, foliate, and filiform papillae. Unlike the other three taste papillae, non-gustatory papillae, filiform papillae cover the entire dorsal surface of the tongue and are important structures for the mechanical stress of sucking. Filiform papillae are further classified into two subtypes with different morphologies, depending on their location on the dorsum of the tongue. The filiform papillae at the intermolar eminence have pointed tips, whereas filiforrn papillae with rounded tips are found in other regions (anterior tongue). It remains unknown how the shape of each type of filiform papillae are determined during their development. Bmp signalling pathway has been known to regulate mechanisms that determine the shapes of many ectodermal organs. The aim of this study was to investigate the role of Bmp signalling in filiform papillae development.
    Design: Comparative in situ hybridization analysis of six Bmps (Bmp2-Bmp7) and two Bmpr genes (Bmpr1a and Bmpr1b) were carried out in filiform papillae development. We further examined tongue papillae in mice over-expressing Noggin under the keratin14 promoter (K14-Noggin).
    Results: We identified a dynamic temporo-spatial expression of Bmps in filiform papillae development. The K14-Noggin mice showed pointed filiform papillae in regions of the tongue normally occupied by the rounded type.
    Conclusions: Bmp signalling thus regulates the shape of filiform papillae. (C) 2011 Elsevier Ltd. All rights reserved.

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  • The role of Irf6 in tooth epithelial invagination 査読

    James Blackburn, Atsushi Ohazama, Katsushige Kawasaki, Yoko Otsuka-Tanaka, Bigang Liu, Kenya Honda, Ryan B. Rountree, Yinling Hu, Maiko Kawasaki, Walter Birchmeier, Ruth Schmidt-Ullrich, Akira Kinoshita, Brian C. Schutte, Nigel L. Hammond, Michael J. Dixon, Paul T. Sharpe

    DEVELOPMENTAL BIOLOGY   365 ( 1 )   61 - 70   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Thickening and the subsequent invagination of the epithelium are an important initial step in Ectodermal organ development. Ikk alpha has been shown to play a critical role in controlling epithelial growth, since Ikk alpha mutant mice show protrusions (evaginations) of incisor tooth, whisker and hair follicle epithelium rather than invagination. We show here that mutation of the Interferon regulatory factor (11) family, Irf6 also results in evagination of incisor epithelium. In common with Ikk alpha mutants, Irf6 mutant evagination occurs in a NF-kappa B-independent manner and shows the same molecular changes as those in Ikk alpha mutants. Irf6 thus also plays a critical role in regulating epithelial invagination. In addition, we also found that canonical Wnt signaling is upregulated in evaginated incisor epithelium of both Ikk alpha and Irf6 mutant embryos. (C) 2012 Elsevier Inc. All rights reserved.

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  • Long-Term Survival in Infantile Malignant Autosomal Recessive Osteopetrosis Secondary to Homozygous p.Arg526Gln Mutation in CLCN7 査読

    Piranit Nik Kantaputra, Saranya Thawanaphong, Witchapong Issarangporn, Phennapha Klangsinsirikul, Atsushi Ohazama, Paul Sharpe, Chayarop Supanchart

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   158A ( 4 )   909 - 916   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Infantile malignant autosomal recessive osteopetrosis (ARO; OMIM 259700) has been reported to be associated with mutations in TCIRG1, CLCN7, or OSTM1. ARO caused by homozygous (or compound heterozygous) mutations in CLCN7, as described here, is usually diagnosed at birth or early in infancy due to generalized osteosclerosis and severe hematologic deficits. The maximal life expectancy of patients with ARO in the absence of bone marrow transplantation is thought to be 10 years. We report on a 25-year-old Thai man who is affected with ARO. Clinical features include proportionate short stature, vision impairment, esotropia, exophthalmos, mild hearing loss, and hepatosplenomegaly. Pancytopenia was present and the patient had frequent illnesses. Radiographs showed generalized osteosclerosis with almost no visible of bone marrow spaces. Dense maxilla and mandible with impacted and malformed teeth were observed. Multiple fractures were reported. He developed osteomyelitis of the mandible on four separate occasions, and partial mandibulectomy was performed. Molecular studies showed that there were no pathogenic mutations in TCIRG1. However, mutation analysis of CLCN7 revealed a homozygous missense mutation (p.Arg526Gln). This patient is, it appears, the longest lived individual with ARO ever reported. Evaluation of osteoclastogenesis in our patient demonstrated very large immature osteoclasts with a high number of nuclei. (C) 2012 Wiley Periodicals, Inc.

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  • Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate 査読

    Andrew D. Economou, Atsushi Ohazama, Thantrira Porntaveetus, Paul T. Sharpe, Shigeru Kondo, M. Albert Basson, Amel Gritli-Linde, Martyn T. Cobourne, Jeremy B. A. Green

    NATURE GENETICS   44 ( 3 )   348 - U163   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.

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  • Histological analysis of the embryonic and adult tooth. 査読

    Ohazama A

    Methods in molecular biology (Clifton, N.J.)   887   1 - 13   2012年

  • Developmental stalling and organ-autonomous regulation of morphogenesis 査読

    Isabelle Miletich, Wei-Yuan Yu, Ruofang Zhang, Kai Yang, Simone Caixeta de Andrade, Silvia Fontes do A. Pereira, Atsushi Ohazama, Orin B. Mock, Georg Buchner, Jane Sealby, Zoe Webster, Minglian Zhao, Marianna Bei, Paul T. Sharpe

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   108 ( 48 )   19270 - 19275   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Timing of organ development during embryogenesis is coordinated such that at birth, organ and fetal size and maturity are appropriately proportioned. The extent to which local developmental timers are integrated with each other and with the signaling interactions that regulate morphogenesis to achieve this end is not understood. Using the absolute requirement for a signaling pathway activity (bone morphogenetic protein, BMP) during a critical stage of tooth development, we show that suboptimal levels of BMP signaling do not lead to abnormal morphogenesis, as suggested by mutants affecting BMP signaling, but to a 24-h stalling of the intrinsic developmental clock of the tooth. During this time, BMP levels accumulate to reach critical levels whereupon tooth development restarts, accelerates to catch up with development of the rest of the embryo and completes normal morphogenesis. This suggests that individual organs can autonomously control their developmental timing to adjust their stage of development to that of other organs. We also find that although BMP signaling is critical for the bud-tocap transition in all teeth, levels of BMP signaling are regulated differently in multicusped teeth. We identify an interaction between two homeodomain transcription factors, Barx1 and Msx1, which is responsible for setting critical levels of BMP activity in multicusped teeth and provides evidence that correlates the levels of Barx1 transcriptional activity with cuspal complexity. This study highlights the importance of absolute levels of signaling activity for development and illustrates remarkable self-regulation in organogenesis that ensures coordination of developmental processes such that timing is subordinate to developmental structure.

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  • Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma 査読

    Akiko Kunita, Takeshi G. Kashima, Atsushi Ohazama, Agamemnon E. Grigoriadis, Masashi Fukayama

    AMERICAN JOURNAL OF PATHOLOGY   179 ( 2 )   1041 - 1049   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Podoplanin is a type-I transmembrane sialomucin-like protein, which is expressed in a wide range of cell types and is involved in platelet aggregation and tumor metastasis. Here, we investigated the function, regulation, and expression of podoplanin in osteosarcoma. Podoplanin expression was observed in three osteosarcoma cell lines (MG-63, HOS, and U-2 OS) with platelet aggregation-inducing ability, which was blocked by podoplanin small-interfering RNA or a neutralizing antibody. Overexpression of podoplanin in nonmetastatic Dunn osteosarcoma cells promoted cell migration without attenuating cell proliferation. Both podoplanin and TGF-beta 1 were up-regulated by c-Fos induction in MC3T3-E1 osteoblastic cells, and were highly expressed in c-Fos transgenic mouse osteosarcomas and c-Fos-transformed osteosarcoma cell lines. Immunohistochemistry of human osteosarcoma tissue microarrays (n = 133) showed staining of tumor cells embedded in an excess of irregular neoplastic bone matrix in 100% of tumors undergoing so-called "normalization/maturation." Podoplanin was also expressed in osteosarcoma subtypes, with 65% of osteoblastic, 100% of chondroblastic, and 79% of fibroblastic tumors. CD44 and pERM immunohistochemistry showed coexpression with podoplanin in both mouse and human osteosarcoma. Podoplanin expression was significantly higher in metastatic Osteosarcomas n = 6) than in primary osteosarcomas = 10). Our data suggest that podoplanin, which is not expressed in normal osteoblasts but in osteocytes, is aberrantly expressed in transformed osteoblasts and in osteosarcoma, and is under AP-1 transcriptional control. Thus podoplanin is a candidate molecule for therapeutic targeting. (Am J Pathol 2011, 170:1041-1049; DOI: 10.1016/j.ajpath.2011.04.027)

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  • The Smallest Teeth in the World are Caused by Mutations in the PCNT Gene 査読

    Piranit Kantaputra, Pranoot Tanpaiboon, Thantrira Porntaveetus, Atsushi Ohazama, Paul Sharpe, Anita Rauch, Atiwat Hussadaloy, Christian T. Thiel

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   155A ( 6 )   1398 - 1403   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We report a follow up study on two MOPD II Thai families with severe dental anomalies and hypoplastic alveolar bone. Striking dental anomalies comprise severe microdontia, opalescent and abnormally shaped teeth, and rootless molars. As a result of severe hypoplastic alveolar bone, most permanent teeth have been lost. Mutation analysis of PCNT revealed 2 novel mutations (p.Lys3154del and p.Glu1154X) and a recurrent mutation (p.Pro1923X). Teeth of the patient who carried a homozygous novel mutation of p.Glu1154X are probably the smallest ever reported. The sizes of the mandibular permanent incisors and all premolars were approximately 2-2.5 mm, mesiodistally. All previously reported, PCNT mutations have been described to cause premature truncation of the pericentrin protein. p. Lys3154del mutation was unique as it was pathogenic as a result of missing only a single amino acid. In situ hybridization of Pcnt shows its expression in the epithelium and mesenchyme during early stages of rodent tooth development. It is evident that PCNT has crucial role in tooth development. The permanent dentition is more severely affected than the one. This implies that PCNT appears to have more role in the development of the permanent dentition. As pericentrin is a critical centrosomal protein, the dental phenotype found in MOPD II patients is postulated to be the consequence of loss of microtubule integrity which leads to defective centrosome function. (C) 2011 Wiley-Liss, Inc.

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  • Expression of fibroblast growth factors (Fgfs) in murine tooth development 査読

    Thantrira Porntaveetus, Yoko Otsuka-Tanaka, M. Albert Basson, Anne M. Moon, Paul T. Sharpe, Atsushi Ohazama

    JOURNAL OF ANATOMY   218 ( 5 )   534 - 543   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Fgf signalling is known to play critical roles in tooth development. Twenty-two Fgf ligands have been identified in mammals, but expression of only 10 in molars and three in the incisor loop stem cell region have been documented in murine tooth development. Our understanding of Fgf signalling in tooth development thus remains incomplete and we therefore carried out comparative in situ hybridisation analysis of unexamined Fgf ligands (eight in molars and 15 in cervical loops of incisors; Fgf11-Fgf14 were excluded from this analysis because they are not secreted and do not activate Fgf receptors) during tooth development. To identify where Fgf signalling is activated, we also examined the expression of Etv4 and Etv5, considered to be transcriptional targets of the Fgf signalling pathway. In molar tooth development, the expression of Fgf15 and Fgf20 was restricted to the primary enamel knots, whereas Etv4 and Etv5 were expressed in cells surrounding the primary enamel knots. Fgf20 expression was observed in the secondary enamel knots, whereas Fgf15 showed localised expression in the adjacent mesenchyme. Fgf16, Etv4 and Etv5 were strongly expressed in the ameloblasts of molars. In the incisor cervical loop stem cell region, Fgf17, Fgf18, Etv4 and Etv5 showed a restricted expression pattern. These molecules thus show dynamic temporo-spatial expression in murine tooth development. We also analysed teeth in Fgf15-/- and Fgf15-/-;Fgf8+/- mutant mice. Neither mutant showed significant abnormalities in tooth development, indicating likely functional redundancy.

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  • Delayed Re-Epithelialization in Periostin-Deficient Mice during Cutaneous Wound Healing 査読

    Takashi Nishiyama, Isao Kii, Takeshi G. Kashima, Yoshinao Kikuchi, Atsushi Ohazama, Masashi Shimazaki, Masashi Fukayama, Akira Kudo

    PLOS ONE   6 ( 4 )   e18410   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background: Matricellular proteins, including periostin, are important for tissue regeneration.
    Methods and Findings: Presently we investigated the function of periostin in cutaneous wound healing by using periostin-deficient (-/-) mice. Periostin mRNA was expressed in both the epidermis and hair follicles, and periostin protein was located at the basement membrane in the hair follicles together with fibronectin and laminin gamma 2. Periostin was associated with laminin gamma 2, and this association enhanced the proteolytic cleavage of the laminin gamma 2 long form to produce its short form. To address the role of periostin in wound healing, we employed a wound healing model using WT and periostin-/- mice and the scratch wound assay in vitro. We found that the wound closure was delayed in the periostin-/- mice coupled with a delay in re-epithelialization and with reduced proliferation of keratinocytes. Furthermore, keratinocyte proliferation was enhanced in periostin-overexpressing HaCaT cells along with up-regulation of phosphorylated NF-kappa B.
    Conclusion: These results indicate that periostin was essential for keratinocyte proliferation for re-epithelialization during cutaneous wound healing.

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  • Lrp4: A Novel Modulator of Extracellular Signaling in Craniofacial Organogenesis 査読

    Atsushi Ohazama, Thantrira Porntaveetus, Masato S. Ota, Joachim Herz, Paul T. Sharpe

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   152A ( 12 )   2974 - 2983   2010年12月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    The low-density lipoprotein (LDL) receptor family is a large evolutionarily conserved group of transmembrane proteins. It has been shown that LDL receptor family members can also function as direct signal transducers or modulators for a broad range of cellular signaling pathways. We have identified a novel mode of signaling pathway integration/coordination that occurs outside cells during development that involves an LDL receptor family member. Physical interaction between an extracellular protein (Wise) that binds BMP ligands and an Lrp receptor (Lrp4) that modulates Wnt signaling, acts to link these two pathways. Mutations in either Wise or Lrp4 in mice produce multiple, but identical abnormalities in tooth development that are linked to alterations in BMP and Wnt signaling. Teeth, in common with many other organs, develop by a series of epithelial-mesenchymal interactions, orchestrated by multiple cell signaling pathways. In tooth development, Lrp4 is expressed exclusively in epithelial cells and Wise mainly in mesenchymal cells. Our hypothesis, based on the mutant phenotypes, cell signaling activity changes and biochemical interactions between Wise and Lrp4 proteins, is that Wise and Lrp4 together act as an extracellular mechanism of coordinating BMP and Wnt signaling activities in epithelial-mesenchymal cell communication during development. (C) 2010 Wiley-Liss, Inc.

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  • Ectoderm, Endoderm, and the Evolution of Heterodont Dentitions 査読

    Atsushi Ohazama, Kim E. Haworth, Masato S. Ota, Roman H. Khonsari, Paul T. Sharpe

    GENESIS   48 ( 6 )   382 - 389   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Mammalian dentitions consist of different shapes/types of teeth that are positioned in different regions of the jaw (heterodont) whereas in many fish and reptiles all teeth are of similar type (homodont). The process by which heterodont dentitions have evolved in mammals is not understood. In many teleosts teeth develop in the pharynx from endoderm (endodermal teeth), whereas mammalian teeth develop from the oral ectoderm indicating that teeth can develop (and thus possibly evolve) via different mechanisms. In this article, we compare the molecular characteristics of pharyngeal/foregut endoderm with the molecular characteristics of oral ectoderm during mouse development. The expression domains of Claudin6, Hnf3 beta, alpha-fetoprotein, Rbm35a, and Sox2 in the embryonic endoderm have boundaries overlapping the molar tooth-forming region, but not the incisor region in the oral ectoderm. These results suggest that molar teeth (but not incisors) develop from epithelium that shares molecular characteristics with pharyngeal endoderm. This opens the possibility that the two different theories proposed for the evolution of teeth may both be correct. Multicuspid (eg. molars) having evolved from the externalization of endodermal teeth into the oral cavity and monocuspid (eg. incisors) having evolved from internalization of ectodermal armour odontodes of ancient fishes. The two different mechanisms of tooth development may have provided the developmental and genetic diversity on which evolution has acted to produce heterodont dentitions in mammals. genesis 48:382-389, 2010. (C) 2010 Wiley-Liss, Inc.

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  • Expression of Fgf signalling pathway related genes during palatal rugae development in the mouse 査読

    Thantrira Porntaveetus, Shelly Oommen, Paul T. Sharpe, Atsushi Ohazama

    GENE EXPRESSION PATTERNS   10 ( 4-5 )   193 - 198   2010年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Fgf signalling plays critical roles in the development of many ectodermal organs. Palatal rugae are ectodermal corrugated structures of the hard palate and in common with other ectodermal appendages, their development is initiated as epithelial thickenings that form placodes as the underlying mesenchymal cells condense. The placode regions then bulge towards to oral cavity to form an overall corrugated appearance. We carried out comparative in situ hybridization analysis of 18 Fgf ligands (Fgf1-Fgf10, Fgf15-Fgf18, Fgf20-Fgf23), four Fgf receptors (Fgfr1-Fgfr4) and four other Fgf signalling related molecules (Spry1, Spry2, Spry4 and Etv5) during murine palatal rugae development. Fgfr1 and Etv5 showed restricted expression in the interplacode epithelium whereas Fgf18 expression was localized to mesenchyme underneath the interplacode epithelium. The expression of Fgf9 was restricted to epithelial ruga placodes whereas Spry4 expression was observed in mesenchyme underneath the placodes. The localized expression of Fgf2, Fgf8, Fgf16, Fgfr4 and Spry1 were found in bulge mesenchyme. Fgf3, Fgf6, Fgfr2 and Spry2 showed expression in the entire epithelium whereas Fgf10 was expressed throughout the mesenchyme. Fgf signalling thus shows dynamic temporo-spatial expression in murine palatal rugae development. (C) 2010 Elsevier B.V. All rights reserved.

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  • A role for suppressed incisor cuspal morphogenesis in the evolution of mammalian heterodont dentition 査読

    Atsushi Ohazama, James Blackburn, Thantrira Porntaveetus, Masato S. Ota, Hong Y. Choi, Eric B. Johnson, Philip Myers, Shelly Oommen, Kazuhiro Eto, John A. Kessler, Takashi Kondo, Gareth J. Fraser, Todd Streelman, Ulyses F. J. Pardinas, Abigail S. Tucker, Pablo E. Ortiz, Cyril Charles, Laurent Viriot, Joachim Herz, Paul T. Sharpe

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   107 ( 1 )   92 - 97   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Changes in tooth shape have played a major role in vertebrate evolution with modification of dentition allowing an organism to adapt to new feeding strategies. The current view is that molar teeth evolved from simple conical teeth, similar to canines, by progressive addition of extra "cones" to form progressively complex multicuspid crowns. Mammalian incisors, however, are neither conical nor multicuspid, and their evolution is unclear. We show that hypomorphic mutation of a cell surface receptor, Lrp4, which modulates multiple signaling pathways, produces incisors with grooved enamel surfaces that exhibit the same molecular characteristics as the tips of molar cusps. Mice with a null mutation of Lrp4 develop extra cusps on molars and have incisors that exhibit clear molar-like cusp and root morphologies. Molecular analysis identifies misregulation of Shh and Bmp signaling in the mutant incisors and suggests an uncoupling of the processes of tooth shape determination and morphogenesis. Incisors thus possess a developmentally suppressed, cuspid crown-like morphogenesis program similar to that in molars that is revealed by loss of Lrp4 activity. Several mammalian species naturally possess multicuspid incisors, suggesting that mammals have the capacity to form multicuspid teeth regardless of location in the oral jaw. Localized loss of enamel may thus have been an intermediary step in the evolution of cusps, both of which use Lrp4-mediated signaling.

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  • Primary cilia regulate Shh activity in the control of molar tooth number 査読

    Atsushi Ohazama, Courtney J. Haycraft, Maisa Seppala, James Blackburn, Sarah Ghafoor, Martyn Cobourne, David C. Martinelli, Chen-Ming Fan, Renata Peterkova, Herve Lesot, Bradley K. Yoder, Paul T. Sharpe

    DEVELOPMENT   136 ( 6 )   897 - 903   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    Primary cilia mediate Hh signalling and mutations in their protein components affect Hh activity. We show that in mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, Shh activity is increased in the toothless diastema mesenchyme of the embryonic jaw primordia. This results in the formation of ectopic teeth in the diastema, mesial to the first molars. This phenotype is specific to loss of polaris activity in the mesenchyme since loss of Polaris in the epithelium has no detrimental affect on tooth development. To further confirm that upregulation of Shh activity is responsible for the ectopic tooth formation, we analysed mice mutant for Gas1, a Shh protein antagonist in diastema mesenchyme. Gas1 mutants also had ectopic diastema teeth and accompanying increased Shh activity. In this context, therefore, primary cilia exert a specific negative regulatory effect on Shh activity that functions to repress tooth formation and thus determine tooth number. Strikingly, the ectopic teeth adopt a size and shape characteristic of premolars, a tooth type that was lost in mice around 50-100 million years ago.

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  • Patterning of molar tooth roots in mammals 査読

    Masato S. Ota, Taka Nakahara, Yoriaki Kanri, Yukishige Kozawa, Atsushi Ohazama, Takaaki Aoba, Takashi Kondo, Sachiko Iseki

    Journal of Oral Biosciences   51 ( 4 )   193 - 198   2009年

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    記述言語:英語   出版者・発行元:Japanese Association for Oral Biology  

    Tooth morphogenesis is regulated by reciprocal interactions between the dental epithelium and odontogenic mesenchyme. As tooth roots are fundamental structures of the tooth support system, the morphology and functions of the roots are very important. However, basic information on the morphology of tooth root patterning and the molecular mechanism of root morphogenesis is largely unavailable. Following tooth crown formation, the dental epithelium forms a double-layered Hertwig's epithelial root sheath (HERS) derived from inner and outer enamel epithelium. Previous studies have reported that HERS plays an important role in tooth root development. Here, we report the correlation between the number of major cusps of the tooth crown and number of tooth roots of first molar and last premolar teeth in several extant mammals. We also discuss the molecular mechanism of tooth root patterning by introducing studies of mouse mutants and human syndromes associated with an abnormal molar morphology.

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  • MAMMALIAN INCISORS RETAIN A CUSPAL MORPHOGENESIS PROGRAMME 査読

    James Blackburn, Atsushi Ohazama, Thantrira Porntaveetus, Joachim Herz, Paul Sharpe

    JOURNAL OF VERTEBRATE PALEONTOLOGY   29   65A - 65A   2009年

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    記述言語:英語   出版者・発行元:SOC VERTEBRATE PALEONTOLOGY  

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  • Lrp4 Modulates Extracellular Integration of Cell Signaling Pathways in Development 査読

    Atsushi Ohazama, Eric B. Johnson, Masato S. Ota, Hong J. Choi, Thantrira Porntaveetus, Shelly Oommen, Nobuyuki Itoh, Kazuhiro Eto, Amel Gritli-Linde, Joachim Herz, Paul T. Sharpe

    PLOS ONE   3 ( 12 )   e4092   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway.

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  • TFII-I gene family during tooth development: Candidate genes for tooth anomalies in Williams syndrome 査読

    Atsushi Ohazama, Paul T. Sharpe

    DEVELOPMENTAL DYNAMICS   236 ( 10 )   2884 - 2888   2007年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Williams syndrome is a rare congenital disorder involving the cardiovascular system, mental retardation, distinctive facial features, and tooth anomalies. It is caused by the heterozygous deletion of similar to 1.6 Mb encompassing 28 genes on human chromosome 7q11.23. It has been suggested that the genes responsible for craniofacial anomalies are located in the telomeric end region, which harbors three members of the TFII-I gene family (Tassabehji et al. [2005] Science 310:1184). To recognize potential candidate genes for the tooth anomalies in Williams syndrome, we carried out comparative in situ hybridization analysis of members of TFII-I gene family during murine odontogenesis. Gtf2i showed widespread expression in the developing head but was higher in the developing teeth than surrounding tissues throughout tooth development. At the bud stage, Gtf2ird1 and Gtf2ird2 were expressed in the epithelial buds. At the early bell stage, expression of Gtf2ird1 and Gtf2ird2 was observed in preameloblasts and preodontoblasts.

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  • Expression of claudins in murine tooth development 査読

    Atsushi Ohazama, Paul T. Sharpe

    DEVELOPMENTAL DYNAMICS   236 ( 1 )   290 - 294   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Claudins belong to a family of transmembrane proteins that were identified as components of tight junction strands. We carried out comparative in situ hybridization analysis of 11 claudin genes (claudin1 - claudin11) during murine odontogenesis from the formation of the epithelial thickening to the cytodifferentiation stage. We identify dynamic spatiotemporal expression of 9 of the 11 claudins. At the early bell stage, two claudins (claudin1 and 4) are specifically expressed in stratum intemedium, whereas only one claudin is expressed in each of the preameloblasts (claudin2) and preodontoblasts (claudin10). At the bud stage, when the first epithelial differentiation pathways are being established, localized expression of six claudins (claudin1, 3, 4, 6, 7, and 10) identify spatial specific interactions, suggesting a hitherto unobserved complexity of epithelial organization, within the early tooth primordium.

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  • Effects of combined treatment with porous bovine inorganic bone grafts and bilayer porcine collagen membrane on refractory one-wall intrabony defects 査読

    J Sakata, H Abe, A Ohazama, K Okubo, C Nagashima, M Suzuki, K Hasegawa

    INTERNATIONAL JOURNAL OF PERIODONTICS & RESTORATIVE DENTISTRY   26 ( 2 )   161 - 169   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:QUINTESSENCE PUBLISHING CO INC  

    The aim of this study was to investigate the effects of a combination of porous bovine inorganic bone graft (Bio-Oss) and bilayer porcine collagen membrane (Bio-Gide) on refractory one-wall intrabony defects in dogs. Bio-Oss and Bio-Gide were applied into the refractory one-wall intrabony defect. The contralateral sites were used as controls (without the application of Bio-Oss and Bio-Gide). At 24 weeks after surgery, similar pocket depths were found in both groups. However, histologic observation revealed an infiltration of inflammatory cells in the control group caused by poor gingival architecture, whereas only a few of the experimental sites showed inflammatory infiltration. In addition to the healthy gingival tissue, periodontal tissue regeneration was observed in the experimental group. The combination of Bio-Oss and Bio-Gide was an effective treatment for refractory one-wall intrabony defects in dogs.

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  • Organized tooth-specific cellular differentiation stimulated by BMP4 査読

    A Ohazama, A Tucker, PT Sharpe

    JOURNAL OF DENTAL RESEARCH   84 ( 7 )   603 - 606   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    Mammalian teeth develop on the oral surface of the first pharyngeal arch by a series of reciprocal interactions between epithelial and mesenchymal cells. The embryonic first pharyngeal arch oral epithelium is able to induce tooth formation when combined with mesenchymal cells from the second pharyngeal arch, a region devoid of tooth development. Second pharyngeal arch mesenchyme is thus competent to form teeth if provided with the correct signals. First- arch oral epithelium expresses several signaling molecules that could be potential inducers of tooth development, including BMP4. The addition of BMP4 to intact second- arch explants resulted in the development of organized structures containing layers of cells that express marker genes of tooth- specific cells, odontoblasts and ameloblasts. Thus, although overt tooth development did not occur, BMP4 has the ability to stimulate organized differentiation of epithelial- and mesenchymal- derived dental- specific cells from non- dental primordia.

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  • [The possibility of tooth regenerative therapy]. 査読

    Ohazama A

    Clinical Calcium   15 ( 7 )   81 - 85   2005年7月

  • TNF signalling in tooth development 査読

    A Ohazama, PT Sharpe

    CURRENT OPINION IN GENETICS & DEVELOPMENT   14 ( 5 )   513 - 519   2004年10月

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    記述言語:英語   出版者・発行元:CURRENT BIOLOGY LTD  

    Mammalian tooth development has served as an excellent model system to investigate the intricate, interactive mechanisms of patterning, morphogenesis and cytodifferentiation during organogenesis. Teeth develop from interactions between epithelium and neural crest-derived (ecto)mesenchyme that are largely mediated by ligand-receptor signalling. It is well-established that signalling molecules of the Bmp, Fgf, Writ and Hedgehog families, are involved at multiple stages of tooth development. Recently, however, a specific role for molecules belonging to the TNF-family of ligands in tooth morphogenesis has been identified, suggesting that this pathway, acting to activate NF-kappaB, has played an important role in the development and evolution of tooth number and shape.

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  • Stem-cell-based tissue engineering of murine teeth 査読

    A Ohazama, SAC Modino, Miletich, I, PT Sharpe

    JOURNAL OF DENTAL RESEARCH   83 ( 7 )   518 - 522   2004年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    Teeth develop from reciprocal interactions between mesenchyme cells and epithelium, where the epithelium provides the instructive information for initiation. Based on these initial tissue interactions, we have replaced the mesenchyme cells with mesenchyme created by aggregation of cultured non-dental stem cells in mice. Recombinations between non-dental cell-derived mesenchyme and embryonic oral epithelium stimulate an odontogenic response in the stem cells. Embryonic stem cells, neural stem cells, and adult bone-marrow-derived cells all responded by expressing odontogenic genes. Transfer of recombinations into adult renal capsules resulted in the development of tooth structures and associated bone. Moreover, transfer of embryonic tooth primordia into the adult jaw resulted in development of tooth structures, showing that an embryonic primordium can develop in its adult environment. These results thus provide a significant advance toward the creation of artificial embryonic tooth primordia from cultured cells that can be used to replace missing teeth following transplantation into the adult mouth.

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  • Opg, rank, and rankl in tooth development: Co-ordination of Odontogenesis and Osteogenesis 査読

    A Ohazama, JM Courtney, PT Sharpe

    JOURNAL OF DENTAL RESEARCH   83 ( 3 )   241 - 244   2004年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

    Osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are mediators of various cellular interactions, including bone metabolism. We analyzed expression of these three genes during murine odontogenesis from epithelial thickening to cytodifferentiation stages. Opg showed expression in the thickening and bud epithelium. Expression of Opg and Rank was observed in both the internal and the external enamel epithelium as well as in the dental papilla mesenchyme. Although Rankl expression was not detected in tooth epithelium or mesenchyme, it was expressed in pre-osteogenic mesenchymal cells close to developing tooth germs. All three genes were detected in developing dentary bone at PO. The addition of exogenous OPG to explant cultures of tooth primordia produced a delay in tooth development that resulted in reduced mineralization. We propose that the spatio-temporal expression of these molecules in early tooth and bone primordia cells has a role in coordinating bone and tooth development.

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  • A dual role for lkk alpha in tooth development 査読

    A Ohazama, YL Hu, R Schmidt-Ullrich, YX Cao, C Scheidereit, M Karin, PT Sharpe

    DEVELOPMENTAL CELL   6 ( 2 )   219 - 227   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    IKKalpha is a component of the IkappaB kinase (IKK) complex that plays a key role in the activation of NF-kappaB. In Ikkalpha mutant mice and mice expressing a transdominant negative mutant Of IkappaBalpha (C-IkappaBalphaDeltaN), molars have abnormal cusps, indicating that Ikka is involved in cusp formation through the NF-kappaB pathway. However, Ikka mutant incisors also have an earlier phenotype where epithelium evaginates outward into the developing oral cavity rather than invaginating into the underlying mesenchyme. A similar evagination of epithelium was also observed in whisker development, suggesting that Ikkalpha contributes to the direction of epithelial growth during the early stages of development in many ectodermal appendages. Since C-IkappaBalphaDeltaN mice have normal incisor epithelial invagination, Ikkalpha's role appears to be NF-kappaB independent. Changes in Notch1, Notch2, Wnt7b, and Shh expression found in incisor epithelium of Ikkalpha mutants suggest that this NF-kappaB-independent function is mediated by Notch/Wnt/Shh signaling pathways.

    DOI: 10.1016/S1534-5807(04)00024-3

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  • Traf6 is essential for murine tooth cusp morphogenesis 査読

    A Ohazama, JM Courtney, AS Tucker, A Naito, S Tanaka, JI Inoue, PT Sharpe

    DEVELOPMENTAL DYNAMICS   229 ( 1 )   131 - 135   2004年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Ectodermal appendages such as skin, hair, teeth, and sweat glands are affected in patients with hypohidrotic (anhydrotic) ectodermal dysplasia (HED). It has been established that mutations in the tumor necrosis factor (TNF) superfamily of molecules, i.e., ectodysplasin (EDA), EDA receptor (EDAR), and EDAR-associated death domain (EDARADD; the intracellular adaptor for EDAR), are responsible for several forms of HED in humans and mice. We show here by in situ hybridisation that another TNF family (orphan) receptor, TROY (also known TAJ, TAJ-alpha, TRADE, and TNFRSF19), is strongly coexpressed with Edar in the epithelial enamel knot signalling centres that are believe to regulate cuspal morphogenesis during murine tooth development. Traf6 is known to function as an intracellular adaptor protein for Troy and examination of Traf6 mutant mice revealed abnormalities in molar teeth that are similar but more severe than those produced by mutations in Eda signalling molecules. This finding suggests that, in additional to ectodysplasin, another TNF pathway involving Troy/Traf6 is involved in molar tooth cusp formation and identifies an essential role for a Traf in tooth development. (C) 2003 Wiley-Liss, Inc.

    DOI: 10.1002/dvdy.10400

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  • Retention of allogenic calvarial periosteum as soft tissue around an allogenic transplanted tooth in alveolar bone 査読

    Kawasaki H, Okamatsu Y, Ohazama A

    Oral Bioscience & Medicine   1   123 - 134   2004年

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  • Overgrowth: Clinical Assessment of 15 Cases. 査読

    Takano T, Ohazama A, Ohtake T, Hasegawa K

    Journal of Showa University Dental Society   24   39 - 46   2004年

  • Expression of TNF-receptor-associated factor genes in murine tooth development 査読

    A Ohazama, JM Courtney, PT Sharpe

    GENE EXPRESSION PATTERNS   3 ( 2 )   127 - 129   2003年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Tumor necrosis factor receptor-associated factors (TRAFs) belong to a family of intracellular adaptor proteins that mediate signaling downstream of various cell surface receptors. We carried out comparative in situ hybridization analysis of five Traf genes Traf1, Traf2, Traf3, Traf4 and Traf6 during murine odontogenesis from the formation of the epithelial thickening to the early bell stage. Traf2, Traf3 and Traf6 showed weak expression in the thickened epithelium. Expression of Traf1, Traf2 and Traf6 were observed in the outer edges of the bud epithelium whereas Traf3 was strongly expressed at the tip of the bud epithelium. Expression of Traf1, Traf4 and Traf6 were detected in the dental papilla mesenchyme. Traf2 showed restricted expression in the internal enamel epithelium of the bell stage while expression of Traf1, Traf3. Traf4 and Traf6 were observed in both the internal and the external enamel epithelium. During early odontogenesis, all five genes show dynamic spatiotemporal expression patterns. (C) 2003 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S1567-133X(03)00028-0

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  • Participation of endogenous IGF-I and TGF-beta 1 with enamel matrix derivative-stimulated cell growth in human periodontal ligament cells 査読

    K Okubo, M Kobayashi, T Takiguchi, T Takada, A Ohazama, Y Okamatsu, K Hasegawa

    JOURNAL OF PERIODONTAL RESEARCH   38 ( 1 )   1 - 9   2003年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL MUNKSGAARD  

    Previous studies have provided the biological basis for the therapeutic use of enamel matrix derivative (EMD) at sites of periodontal regeneration. A purpose of this study is to determine effects of EMD on cell growth, ostcoblastic differentiation and insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-beta1) production in human periodontal ligament cells (HPLC). We also examined participation of endogenous IGF-I and TGF-beta1 with EMD-stimulated cell growth in these cells. HPLCs used in this study were treated with EMD alone or in combination with antihuman IGF-I antibody (anti-hIGF-I) or anti-hTGF-beta1, recombinant human bone morphogenetic protein-2 (rhBMP-2), 1,25-dihydroxyvitamin D-3[1,25(OH)(2)D-3], rhTGF-beta1 or rhIGF-I. After each treatment, cell growth, the production of IGF-I and TGF-beta1 and the expression of osteoblastic phenotypes were evaluated. EMD stimulated cell growth in dose-dependent and time-dependent manners. EMD was also stimulated to express IGF-I and TGF-beta1 at protein and mRNA levels. The EMD-stimulated cell growth was partially suppressed by cotreatment with anti-hIGF-I or anti-hTGF-beta1, and cell growth was also stimulated by treatment with rhIGF-I or rhTGF-beta1. rhBMP-2 stimulated alkaline phosphatase (ALPase) activity and ALPase mRNA expression, and 1,25(OH)(2)D-3 stimulated ALPase and osteocalcin mRNA expression. However, EMD showed no effect on the osteoblastic phenotypes expression. These results demonstrated that EMD has no appreciable effect on osteoblastic differentiation, however it stimulates cell growth and IGF-I and TGF-beta1 production in HPLC, and that these endogenous growth factors partially relate to the EMD-stimulated cell growth in HPLC.

    DOI: 10.1034/j.1600-0765.2003.01607.x

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  • Tooth development is independent of a Hox patterning programme 査読

    CT James, A Ohazama, AS Tucker, PT Sharpe

    DEVELOPMENTAL DYNAMICS   225 ( 3 )   332 - 335   2002年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Hox genes have a critical role in controlling the patterning processes of many tissues by imparting positional information in embryogenesis. Patterning of the pharyngeal component of the skull (the visceroskeleton) has been proposed to be influenced by this "Hox code." Recently, it has been shown that Hox genes are associated with the evolution of jaws, loss of Hox gene expression in the first branchial arch being necessary for the transition from the agnathan condition to the gnathostome condition. Teeth develop on the first branchial arch in mammals and, therefore, might be expected to be under the control of Hox genes in a manner similar to that of the cranial skeletal elements. However, we show that, unlike cartilage and bone, the development of teeth is not affected by alterations in Hoxa2 expression. Tooth development in the first arch was unaffected by overexpression of Hoxa2, whereas recombinations of second arch mesenchyme with first arch epithelium led to tooth development within a Hoxa2-positive environment. These data demonstrate that teeth develop from local interactions and that tooth formation is not under the axial patterning program specified by the Hox genes. We propose that the evolutionary development of teeth in the first branchial arch is independent of the loss of Hox expression necessary for the development of the jaw. (C) 2002 Wiley-Liss, Inc.

    DOI: 10.1002/dvdy.10168

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  • Participation of periodontal ligament cells with regeneration of alveolar bone 査読

    J Isaka, A Ohazama, M Kobayashi, C Nagashima, T Takiguchi, H Kawasaki, T Tachikawa, K Hasegawa

    JOURNAL OF PERIODONTOLOGY   72 ( 3 )   314 - 323   2001年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ACAD PERIODONTOLOGY  

    Background: It is important to clarify the participation of periodontal ligament (PDL) cells in the regeneration of alveolar bone to establish a reliable approach for obtaining periodontal regeneration. The aim of this study was to determine whether PDL cells play an important role in alveolar bone repair during the course of periodontal regeneration.
    Methods: In an in vitro study, the expression of the osteoblast phenotype, such as alkaline phosphatase activity and parathyroid hormone-dependent 3',5'-cyclic adenosine monophosphate accumulation, was investigated in dog PDL cells (DPLC) and dog bone cells isolated from mandibles (DBC). In a related study, the roots of mandibular third premolars extracted from aged dogs were divided into a PDL(+) group, in which the PDL was preserved, and a PDL(-) group, in which the PDL was removed. These roots were respectively transplanted into surgically created bone cavities with buccal and interproximal bone defects in an edentulous area, prepared in advance by extraction of mandibular fourth premolars. These bone defects with the transplanted roots were completely covered with submerged physical barrier membranes. New bone formation and new connective tissue attachment, which require new cementum and insertion of functionally oriented new collagen fibers of periodontal ligament, were histomorphometrically assessed, and were compared between the PDL(+) and PDL(-) groups 6 weeks after transplantation.
    Results: Both cultured DPLC and DEC exhibited the osteoblast phenotype. New connective tissue attachment was observed only in the PDL(+) group. However, alveolar bone was almost completely regenerated to the original bone height in both the PDL(+) and PDL(-) groups, and the amount of newly formed bone was not significantly different between the 2 groups.
    Conclusions: DPLC retain the capability to differentiate into an osteoblast lineage and may act in the regeneration of periodontal ligament with new cementum formation, whereas these cells may have a limited influence on alveolar bone formation during the course of periodontal regeneration.

    DOI: 10.1902/jop.2001.72.3.314

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  • Periodontal tissue regeneration using fibrin tissue adhesive material. 査読

    Ohazama A, Hatayama J, Okamatsu Y, Isatsu K, Tachikawa T, Hasegawa K

    Periodontal Clinical Investigations   18   26 - 38   1996年

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MISC

  • Reptinは胎仔上皮におけるDNA損傷応答を介して器官形成を制御する

    目黒史也, 目黒史也, 目黒史也, 柿原嘉人, 川崎真依子, 川崎勝盛, 川崎勝盛, 丹原惇, 丹原惇, トゥラカナン スッパラック, 工藤武久, 工藤武久, 山田茜, 山田茜, 前田健康, 多部田康一, 佐伯万騎男, 大峡淳

    新潟歯学会雑誌   50 ( 2 )   2020年

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  • ラット間葉系細胞の多面的骨誘導能に対する低酸素処理の効果に関する検討

    齋藤 直朗, 泉 健次, 秋葉 陽介, 加藤 寛子, 原 夕子, 小島 拓, 芳澤 享子, 小林 正治, 大峡 淳, 前田 健康

    新潟歯学会雑誌   45 ( 2 )   106 - 106   2015年12月

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    記述言語:日本語   出版者・発行元:新潟歯学会  

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  • the buccohypophyseal canal is an ancestral vertebrate trait maintained by modulation in sonic hedgehog signaling (vol 11, 27, 2013)

    Roman H. Khonsari, Maisa Seppala, Alan Pradel, Hugo Dutel, Gael Clement, Oleg Lebedev, Sarah Ghafoor, Michaela Rothova, Abigael Tucker, John G. Maisey, Chen-Ming Fan, Atsushi Ohazama, Paul Tafforeau, Brunella Franco, Jill Helms, Courtney J. Haycraft, Albert David, Philippe Janvier, Martyn T. Cobourne, Paul T. Sharpe

    BMC BIOLOGY   11   2013年6月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    DOI: 10.1186/1741-7007-11-70

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  • A dual role for IKK alpha tooth development

    P. T. Sharpe, K. E. Haworth, A. Ohazama

    JOURNAL OF DENTAL RESEARCH   82   B305 - B305   2003年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

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  • C-19-16 : 30 エナメルマトリックスタンパクが歯根膜細胞の分化、増殖に与える影響

    大久保 敬吾, 小林 誠, 大峡 淳, 滝口 尚, 岡松 良昌, 出口 勝敏, 長谷川 紘司

    日本歯周病学会会誌   42   156 - 156   2000年9月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人日本歯周病学会  

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  • Is bone regeneration affected by presence of periodontal ligament?

    C Nagashima, A Ohazama, T Takiguchi, H Kawasaki, M Kobayashi, T Tachikawa, K Hasegawa

    JOURNAL OF DENTAL RESEARCH   77 ( 5 )   1305 - 1305   1998年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC DENTAL RESEARCH  

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共同研究・競争的資金等の研究

  • 口蓋形成におけるX染色体の不活性化の検索

    研究課題/領域番号:23K18354

    2023年6月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    大峡 淳, 川崎 勝盛, 川崎 真依子

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

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  • 歯の形成におけるDNA損傷/修復のメカニズムの解明

    研究課題/領域番号:23K09434

    2023年4月 - 2026年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    川崎 真依子, 大峡 淳, 川崎 勝盛

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

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  • 上顎正中過剰歯の発生メカニズムの解明

    研究課題/領域番号:21K10182

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    川崎 勝盛, 前田 健康, 大峡 淳

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    過剰歯の出現機構は古くから研究対象とされ、その原因にさまざまな仮説が提唱されてきたが、確定的な証拠は提示されていない。我々は一次繊毛の構成タンパクの一つであるOfd1の顎顔面形成過程における役割を解明するために遺伝子改変マウスを作成し、解析中、上顎正中部に過剰歯胚が形成されていることに気づいた。これまで正中過剰歯のモデル動物は報告されておらず、これを解析することで正中過剰歯出現機構が解明されるのではないかと考えた。
    本Odf1遺伝子改変マウスの過剰歯胚の経日的組織学解析の結果から、歯胚蕾状期では野生型と比較して、差は認められなかったものの、帽状期以降、通常歯胚とは別に過剰歯歯胚が生じているのを確認した。過剰歯は鐘状期にかけて正常歯胚とおもに成長を示すが、その成長方向は正常歯胚とは異なっていた。
    また、神経堤由来細胞にGFPを発現させたOdf1遺伝子改変マウスの解析から、過剰歯歯胚が生じる際、神経堤由来細胞の局在が、野生型マウスとは異なることを見出した。

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  • 下顎骨形成メカニズムの解明

    研究課題/領域番号:21K10088

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    石田 陽子, 前田 健康, 大峡 淳, 川崎 勝盛

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    先天異常の3分の1で、顎顔面になんらかの異常が存在すると言われている。その中でも、下顎が小さい小下顎症は高頻度で認められる先天異常の一つである。ピエール・ロバン症候群やトリーチャー・コリンズ症候群などの遺伝性疾患だけでなく、非家族性の小下顎症も多く認められる。小下顎症を有する患者が、他の部位の骨に症状を有するケースは少ない。つまり、小下顎症を有する多くの患者は、下顎の骨の発生にのみ異常をきたしている。異常の頻度が高いことは、下顎骨の発生が、わずかな変異にも敏感に反応するほど精巧な分子制御メカニズムで成り立っていることを意味しているが、なぜ下顎の骨だけが、その様な繊細な分子機構によって形成されるのかは明らかにされていない。Oral-facial-digital type I (OFDI)症候群は、小下顎症を示す疾患の一つであり、その原因遺伝子としてOfd1が同定されている。顎顔面の骨を形成する神経堤由来細胞でOfd1を欠損させたマウス(Ofd1fl/fl;Wnt1Creマウス)を作成したところ、小下顎症が確認された。Ofd1は一次線毛に局在するタンパクである。一次線毛はWntシグナルに関与するが、Ofd1fl/fl;Wnt1Creマウスの下顎形成領域にWntシグナルマーカーの変化は認められなかった。

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  • 皮膚の付属器官発生における老化活性の機能解明

    研究課題/領域番号:21H03122

    2021年 - 2024年

    制度名:基盤研究(B)

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    大峡 淳(代表者)

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    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    歯の再生は、21世紀で成し遂げるべき医療であり、その実現には幹細胞の利用が欠かせない。しかし、幹細胞の歯胚細胞への正しい分化誘導という最も重要な部分の解決が未だなされていない。一般に、器官発生は、胎生幹細胞が少しずつ、より細かな方向へ運命決定をしていくことで達成される。歯は、毛髪などと同じ皮膚の付属器官に属する。全ての皮膚の付属器官が先天的に欠如する遺伝性疾患の存在は、胎生幹細胞がダイレクトに歯胚細胞へ分化するのではなく、皮膚の付属器官への運命決定を行った後に、歯胚細胞への分化を決定している事を示している。胎生幹細胞を、どの付属器官へ分化させるかを決定するメカニズムは、歯の再生における幹細胞の歯胚細胞への分化誘導と同義であるが、未だ明らかでない。胎生期の形成途中の歯胚と毛包に老化シグナルを見出した。さらに老齢マウスの前歯に、異所性の毛髪の形成を認めた。

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  • 代生歯堤の形成・維持メカニズムの解明

    2021年 - 2022年

    制度名:挑戦的研究(萌芽)

    大峡 淳(代表者)

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    担当区分:研究代表者 

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  • 舌誘導メカニズムの解明

    研究課題/領域番号:20K10156

    2020年4月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    丹原 惇, 大峡 淳, 齊藤 一誠

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    舌は、歯科領域で最も癌が発生する部位であり、口腔内で手術によって最も除去される器官とも言える。そのため、舌の再生療法の確立が期待されている。しかし、再生療法確立に必須となる幹細胞の舌への誘導メカニズムが解明されていない。それは、幹細胞誘導に必要な舌の発生メカニズムが明らかになっていないことに起因しており、舌の発生研究の進展が望まれている。器官の発生メカニズムの解明には、目的の器官に異常の存在する実験動物が必須であるものの、舌に異常を持つ遺伝子欠損マウスの報告は多くない。我々は神経堤由来細胞特異的にmicroRNAが欠損したマウスにおいて、舌がほとんど形成されていないことを見出した。本研究は、microRNA欠損マウスの解析から、舌の発生メカニズムを解明することを目的としている。著しく減形成したmicroRNA欠損マウスの舌に筋肉が存在するか、筋細胞マーカーであるMyf5で確認した。野生型マウスでは、Myf5発現細胞と、Myf5非発現細胞が、特定の配列で認められたのに対し、microRNA欠損マウスでは減形成舌の表層にMyf5非発現細胞が、その下方にMyf5発現細胞が認められ、野生型とは異なる配列を示した。

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  • 顎顔面の発生過程における一次繊毛の機能解明:シグナル経路のクロストークの観点から

    研究課題/領域番号:20K10092

    2020年4月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    川崎 真依子, 前田 健康, 大峡 淳, 川崎 勝盛

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    一次繊毛 primary ciliaは発生過程に関わる主要なシグナルの制御に関わり、その機能不全は顎顔面形成異常を伴う繊毛病を引き起こす。しかし、顎顔面形成における一次繊毛内での各種シグナル間の相互作用や、複数シグナルによる器官形成制御については未解明のままである。その原因の1つとして複数のシグナルを同時にターゲットとする研究がなされていないことがあげられる。本研究課題は、SHHとWNTシグナル経路を同時に変化させることによって引き起こる形態学的、分子的手法変化を解析することにより、顎顔面発生における一次繊毛の複数シグナル制御の機能を明らかにすることである。今年度は、SHHシグナルを間葉の組織特異的に欠損させ、WNTシグナルを間葉の組織特異的に過剰発現させたマウスの作成とその表現型の解析を行った。SHHシグナルを間葉の組織特異的に欠損させると同時にWNTシグナルを間葉の組織特異的に過剰発現させたマウスは、SHHシグナルを間葉の組織特異的に欠損させたマウスと一部異なる顎顔面領域の異常を示した。顔面の幅径の増加、および歯の形成遅延、眼瞼の形成異常などが挙げられ、これは、WNTシグナルが間葉で過剰発現していることが影響している可能性が示唆された。

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  • Shhシグナルによるアクトミオシン細胞内張力を介した歯の形態形成の新たな制御機構

    研究課題/領域番号:19K10047

    2019年4月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    山中 淳之, 中富 満城, 大峡 淳

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    Sonic hedgehog (Shh) は、歯の発生過程の開始期から形態形成期に至るまで、主に歯胚上皮に強く発現するシグナル分子である。これまでに、mRNAの発現パターン、歯胚の器官培養実験、ノックアウトマウスの表現型の解析などから、Shhの役割に関する多くの知見が得られている。しかし、一つにはShhが複数の別のシグナル経路と相互に関連しあっているために、また、Shhが継続して発現するので発生のステージごとに違う機能が考えられるために、歯胚の細胞の挙動に対する具体的な機能は不明なままである。本研究の目的は、歯胚上皮におけるアクトミオシン細胞骨格を介した細胞張力をShhシグナルが調節していることを証明することである。
    そのために、マウスの歯胚を材料に、(I) 歯胚の器官培養を利用したShh阻害剤添加実験、(II) 口腔上皮特異的なShh遺伝子欠損 (KO) マウスを使った歯胚の表現型解析、を計画した。2021年度までに、(I)の器官培養実験はほぼ完了した。しかし、 (II)のマウスの解析に関しては、Shhfl/flマウスを導入する予定であったが、Jackson社がlive mouseの提供を中止したため、実行できない状況になった。
    そこで、臼歯の形態が異なるマウスとトガリネズミ(スンクス)の歯冠の形態形成を比較することで、Shhの発現の違いが形態の違いに及ぼす影響を調べる実験を追加した。マウスの臼歯では咬頭が丘陵のような鈍頭型を示すのに対して、トガリネズミでは鋭い山頂のような尖頭型を示す。Shh, Wnt10, Edar, Fgf4などの発現パターンの違いを追跡し、細胞接着因子や細胞骨格の局在との関係を調べた。さらに、トガリネズミの歯胚の器官培養を用いたShh阻害実験を行い、咬頭形成におけるShhの機能を調べている。この実験は現在も継続中であるため、研究期間を1年延長した。

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  • DNA修復機構に着目した顎顔面領域における先天異常発生メカニズムの解明

    研究課題/領域番号:19H03849

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    前田 健康, 佐伯 万騎男, 大峡 淳, 柿原 嘉人

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    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    DNA修復機構は細胞生存に必要不可欠なプロセスである。発生過程で、DNA修復機構が必要であるかは不明である。本研究ではDNA修復分子であるReptinに着目し、上皮特異的なReptin欠損マウスを作成したところ、頭部をはじめとする皮膚表皮の形成が抑制されていた。表皮におけるDNA損傷と、それによって活性化されたp53/p21シグナルによる細胞増殖停止が原因であった。正常な皮膚の発生において、酸化ストレスにより表皮のDNAが一時的に損傷されることが示された。皮膚は、発生中に生じる酸化ストレスによって引き起こされた損傷DNAをReptinにより修復することで、正常に発生することが示唆された。

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  • 意図的細胞誘導による新規エナメル上皮腫治療法開発に向けた試み

    研究課題/領域番号:18K19639

    2018年6月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    前田 健康, 大峡 淳, 川崎 勝盛, 川崎 真依子

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    配分額:6370000円 ( 直接経費:4900000円 、 間接経費:1470000円 )

    エナメル芽細胞は、退縮期に入るとほとんどの活性を失い、歯の萌出とともに体外に排出される。エナメル上皮腫は、胎生期のエナメル器の細胞が残存し腫瘍化したものである。エナメル上皮腫の細胞を退縮エナメル上皮細胞に類似した細胞に分化誘導することによって、エナメル上皮腫の進行が抑制される可能性がある。しかしながら、退縮エナメル上皮の分子レベルでの知見はほとんどない。本研究では、退縮エナメル上皮は、老化シグナルを活性させることによって活性を低下させ、萌出までエナメル表面にとどまることを明らかにした。

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  • 顎関節形成の包括的分子機構の解明

    研究課題/領域番号:18K09762

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    川崎 勝盛, 前田 健康, 大峡 淳, 川崎 真依子

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    顎関節は遺伝子改変マウスで異常が現れにくく、発生メカニズムが解明されていない器官である。本研究では一次繊毛関連タンパクであるIft88に着目し、間葉組織特異的Ift88欠損マウスを作成したところ、顎関節の異常を認めた。検索の結果、間葉組織特異的Ift88欠損マウスにおける顎関節の異常は、顎骨の異常が起因であり、その顎骨の異常はShhシグナルの低下によるものであることが明らかとなった。

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  • 口蓋突起誘導メカニズムの解明

    研究課題/領域番号:17K11829

    2017年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    川崎 真依子, 前田 健康, 大峡 淳, 川崎 勝盛

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    本研究は、一次繊毛の機能と形成に関わるOfd1とIft88の欠損マウスを用いて、一次繊毛の口蓋形成メカニズムへの役割を解明することを目的とする。Ofd1とIft88の神経堤由来細胞特異的欠損マウスで口蓋裂を認めた。さらに両欠損マウスの口蓋突起予定領域には、異所性の骨形成とアポトーシスが認められた。しかしながら、アポトーシスを抑制して異所性の骨形成は消失しても、口蓋裂に変化は認められなかった。以上より、Ofd1とIft88は、アポトーシスを抑制することにより、上顎骨形成過程において骨形成を制御しており、この機構は口蓋突起の形成とは独立したものであることが示された。

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  • 過剰歯から考える歯種決定のメカニズム

    研究課題/領域番号:17K11957

    2017年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    齊藤 陽子, 齊藤 一誠, 大峡 淳, 佐藤 正宏

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究はヒトにおける過剰歯を分子生物学的手法と形態学的手法を用いて解析することが特徴である。形態学的アプローチとしてマイクロCTによる解析を行い、過剰歯の内部構造を主体に解析するために歯髄腔のみを硬組織構造より分離、抽出して解析することに成功した。
    一方、分子生物学的手法による解析結果では、ヒト過剰歯の咬頭数はマウスの場合とは異なる遺伝子による制御の可能性が示唆された。

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  • 口蓋裂発症へのエピジェネティクスの関与の解明

    研究課題/領域番号:17K11954

    2017年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    石田 陽子, 前田 健康, 大峡 淳, 川崎 勝盛

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    口唇口蓋裂は最も頻度の高い先天性疾患の一つであるが、その多くが非家族性かつ非症候群であり、その非ゲノム的な原因は不明なままである。本研究ではmicroRNA形成に重要な役割を果たすDicerに着目し、間葉組織特異的Dicer欠損マウスを作成し、解析を行った。その結果、間葉組織特異的Dicer欠損マウスにおいて下顎正中に裂を認めた。この正中では、細胞死が亢進しており、遺伝子学的検索の結果、Shh関連遺伝子であるGli1の発現が有意に減少していた。以上の事からDicer間葉特異的欠損マウスの下顎正中の裂は、microRNAの欠損によるShhシグナルの活性が抑制されたことによるものと示唆された。

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  • 分化機構解明による幹細胞の意図的誘導法の開発

    2017年 - 2019年

    制度名:基盤研究(A)

    大峡 淳(代表者)

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    担当区分:研究代表者  資金種別:競争的資金

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  • 「生体完結型再生療法」開発への挑戦

    2017年 - 2019年

    制度名:挑戦的研究(開拓)

    大峡 淳(代表者)

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    担当区分:研究代表者  資金種別:競争的資金

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  • p53遺伝子欠損コンソミックマウスを用いた口蓋裂発症メカニズム解析

    研究課題/領域番号:16H05539

    2016年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    高木 律男, 大峡 淳, 児玉 泰光

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    配分額:12610000円 ( 直接経費:9700000円 、 間接経費:2910000円 )

    今回、CL/Fr 系統マウスを用いて、primary cleft palate とsecondary cleft palateに分子レベルでの違いが存在するか解析したところ、primary cleft palateでは、ShhとWntのシグナルの低下が確認されたが、secondary cleft palate領域では、それらのシグナルに変化は認められなかった。以上のことより、primary cleft palateとsecondary cleft palateは、別々のメカニズムでひき起こる可能性があることが示唆された。

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  • 歯の再生療法に向けた幹細胞分化制御機構の解明~毛との相同性、異同性に着目して~

    研究課題/領域番号:16H05532

    2016年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    前田 健康, 大峡 淳, 川崎 勝盛, 川崎 真依子, 井上 佳世子

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    NF-kBが過剰活性化するIkkβ-K5マウスを用いた解析で、エナメル芽細胞の断裂や歯髄内における異所性の硬組織形成後、幹細胞ニッチであるcervical loopに形態変化が生じた。cervical loopは複数形成され、Sox2の上昇から幹細胞系細胞の増加であることが認められた。その後、異所性の毛髪、異所性のエナメル質形成、過剰歯が同時に引き起こされた。NF-kBの過剰活性により幹細胞ニッチが増加し、各幹細胞が違う組織へと分化することが示された。一方、幹細胞ニッチの周囲細胞にNF-kBの上昇が認められ、幹細胞の分化と増殖が周囲の細胞により制御されていることが示唆された。

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  • 遺伝子改変マウスを用いた歯誘導メカニズムの網羅的解析

    研究課題/領域番号:16K11783

    2016年4月 - 2018年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    原田 史子, 前田 健康, 大峡 淳, 川崎 真依子

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究の目的は,歯数を決定するメカニズムを解明するため,歯数の制御に関わる歯の発生開始誘導機構を解明することにある.口腔内で歯の欠損と過剰歯が同時に生じるヒト口顔指症候群Ⅰの原因遺伝子Ofd1に着目し,その欠損マウスを作成,解析を行った.
    Cre-LoxPシステムを用い Ofd1を上皮および間葉特異的に欠損させたマウスを作成した. Ofd1上皮特異的欠損マウスでは, 歯数の異常は認められなかった.一方,ホモ型のOfd1間葉特異的欠損マウスでは, 上下顎前歯歯胚が蕾状期で停止し, 上顎臼歯の舌側に過剰歯を認めた.ヘテロ型のOfd1間葉特異的欠損マウスでは, 正常な前歯, 前歯歯胚の停止,上下顎臼歯部の舌側の過剰歯が混在した.これらにより間葉のOfd1が,歯数制御に必須であることが明らかとなった.マイクロアレイやin situ hybridizationを行った結果,ホモ型のOfd1間葉特異的欠損マウス間葉にShhシグナルの著しい低下が確認された.ヘテロ型のOfd1間葉特異的欠損マウスの間葉では, Shhシグナルの活性部位と活性欠如部位がモザイク状に混在した.そこで,Shhシグナル活性に不可欠なSmoの間葉特異的欠損マウスを作成,解析した.その結果,Smo間葉特異的欠損マウスでは, 下顎前歯歯胚は蕾状期で停止し,下顎前歯部に 蕾状期で停止した過剰歯を認め,臼歯部の舌側に過剰歯を認めた.上顎前歯は存在したが,上顎臼歯は存在せず,臼歯部頬側に過剰歯が確認された.
    以上のことから,Ofd1間葉特異的欠損マウスではShhシグナルの低下にも関わらず, ホモ型およびヘテロ型のOfd1間葉特異的欠損マウスと,Smo間葉特異的欠損マウスの歯の表現系は一部のみでしか一致しなかった.このことは,Ofd1による歯数制御はShhシグナルのみではなく複数の分子を介して行われる可能性を示唆する.

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  • 分子解析による赤唇発生機構の解明~再生に向けた展開研究~

    研究課題/領域番号:16K15773

    2016年4月 - 2018年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的萌芽研究

    提供機関:日本学術振興会

    前田 健康, 大峡 淳, 井上 佳世子

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    配分額:3510000円 ( 直接経費:2700000円 、 間接経費:810000円 )

    赤唇はヒト特有の組織で、その再建は審美的にも重要である。しかしながら、その特殊性のため、実験動物を用いた研究は不可能である。本研究では赤唇の組織特殊性を解明するために、成人の赤唇にいかなる分子が発現しているかを検討した。赤唇部には、long noncoding RNA(lncRNA)、small nuclear RNA(snRNA)が、粘膜部よりも多く認められ、またホメオボックスを有するPAX遺伝子の発現が認められた。粘膜部に発現せず、赤唇部にのみ強く発現していた分子として、PPDPFなどが確認された。赤唇の特殊性は粘膜部とは非常に違う分子機構により制御されている可能性を示唆している。

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  • ヘッジホッグシグナル伝達系は末梢神経再生を誘導する

    研究課題/領域番号:15H05041

    2015年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    瀬尾 憲司, 前田 健康, 大峡 淳, 紙谷 義孝, 藤原 直士

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    配分額:16900000円 ( 直接経費:13000000円 、 間接経費:3900000円 )

    末梢神経が損傷するとソニックヘッジホッグ(Shh)とその転写因子Gli1が神経損傷部に発現する。Shhシグナル系を抑制すると、再生軸索は異常に走行し、軸索結合は障害される。さらに中枢側断端の幼若シュワン細胞数を増加させ、末梢側でマクロファージ数を減少させる。損傷後の経過では、Shhの発現は損傷後早期に上昇し後期に減衰するが、Dhhは損傷後早期に発現量が低下し後期になると上昇する。Ihhは損傷前後では発現しない。すなわち損傷を契機にDhhシグナルからShhシグナルへのスイッチングが起こっている。
    以上の結果から損傷神経の再生にはShh,Dhhが重要な役割をしていることが示唆された。

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  • p53ノックアウトマウス人工授精凍結胚を用いた口蓋裂発生メカニズムの解析

    研究課題/領域番号:15K11237

    2015年4月 - 2018年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    児玉 泰光, 大峡 淳

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    がん抑制遺伝子として知られるp53 遺伝子を「奇形発生の番人」と捉え、CL/Fr 系統マウス(口唇口蓋裂感受性系統)における口唇口蓋裂形成へのp53の影響を検索することを目的に「p53ノックアウトCL/Fr 系統マウス人工授精凍結胚」を用いて解析を行った。
    CL/Fr;p53(-/-)マウスにおける口唇裂は、これまでに報告のない特異的な形態異常が原因と示唆された。CL/Fr;p53(-/-)マウスにおける口蓋裂は、いわゆる完全口蓋裂の病態に近く、口蓋突起は認められるものの、その大きさは非常に小さく、水平方向への増殖はほとんど生じていないことが判明した。

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  • ヒト顎関節オルガノイド作製への挑戦

    研究課題/領域番号:15K15674

    2015年4月 - 2017年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的萌芽研究

    提供機関:日本学術振興会

    井上 佳世子, 前田 健康, 大峡 淳, 河野 芳朗

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    顎関節原基オルガノイドを作製するには,顎関節の発生における分子メカニズムの理解が必須である.しかし,その基礎となる顎関節の発生初期における各構成体の出現時期や部位にも,未だ不明な点は多い.本研究ではマウス胎仔の体重を基準として顎関節の発生の正確な開始時期と部位の同定が可能であることを明かにした.また顎関節形成予定領域に Runx2とSox9の発現が認められ,その3次元解析から,下顎頭原基は下顎体と連続して発生することが示唆された.一方,顎関節の母体外発生誘導法として各種器官培養法を検討したが,現行の改良法では正常な顎関節の発育が継続されず,新規培養法の開発が必要であることが示された.

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  • 口蓋粘膜の歯形成上皮へのリプログラミング

    研究課題/領域番号:26670848

    2014年4月 - 2016年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的萌芽研究

    提供機関:日本学術振興会

    前田 健康, 大峡 淳, 井上 佳世子

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    歯と口蓋皺壁の発生中における発現分子の違いを、マウスを用いて検索した。口蓋皺壁の間葉は、歯胚と同様に、神経堤由来であることが確認された。口蓋皺壁の発生中に、Bmp4やLrp4等多くの歯の関連遺伝子の発現が認められ、Shh、Bmp等の歯の発生で認められるシグナルも発生中の口蓋皺壁で活性化していた。一方、Msx1は口蓋皺壁発生で発現していなかった。口蓋皺壁に発現する遺伝子の改変マウスでも口蓋皺壁の走行に異常が認められた。

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  • 幹細胞の分化制御機構の解明の基盤研究 〜NF-kBからの解析〜

    2014年 - 2016年

    制度名:基盤研究(B)

    大峡 淳(代表者)

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    担当区分:研究代表者  資金種別:競争的資金

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  • 歯の発生における時間軸変更への挑戦

    2014年 - 2015年

    制度名:挑戦的萌芽研究

    大峡 淳(代表者)

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    担当区分:研究代表者  資金種別:競争的資金

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  • 歯根膜ルフィニ神経終末の発生・再生に関わる新規イオンチャネルの役割

    研究課題/領域番号:23390418

    2011年4月 - 2014年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    前田 健康, 泉 健次, 井上 佳世子, 河野 芳朗, 大峡 淳, 鈴木 晶子, 原田 史子, 吉居 朋子, 井表 千馨

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    配分額:18850000円 ( 直接経費:14500000円 、 間接経費:4350000円 )

    acid-sensing ion channel 3 (ASIC3) familyに着目して歯根膜ルフィニ神経終末の再生過程を検討した。下歯槽神経切断実験における歯根膜ルフィニ神経終末および三叉神経節におけるASIC3の発現パターンから、ASIC3は三叉神経節における神経再生中の神経活性の調節、すなわちneuron-glia interactionに関与することが示唆された。

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  • 外胚葉器官形成におけるNF-kBのメカニズム解明

    研究課題/領域番号:16592080

    2004年 - 2005年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    大峡 淳

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    配分額:3600000円 ( 直接経費:3600000円 )

    転写因子であるNF-kBは、癌、炎症反応、免疫応答、内分泌系など様々な生体反応に関与している。本研究において我々は、このNF-kBの歯の発生への関与についての検討を行い、以下の結果を得た。NF-kBのインヒビターをリン酸化し、NF-kBの活性を促すIKKの構成成分の1つであるIkkαのノックアウトマウスの前歯に異常が認めれ、その前歯歯胚においてNotchの発現が抑制されている事が明らかとなってる。このNotchは、歯胚に発現するものの、その発現は、Stellate Reticulum(SR)に限られる。これは、Ikkαのノックアウトマウスの前歯におけるNotchの抑制が、Notchの抑制ではなく、SRの欠如である可能性がある事を示している。そこでIkkαのノックアウトマウスの前歯におけるSRの有無を検索した。SRのマーカーであるSLUG、CD44のIkkαのノックアウトマウスの前歯での発現が確認できた。またSRは、Msx2を通して、エナメル形成に関与する事が報告されている。Ikkαのノックアウトマウスの前歯において、Msx2および正常なエナメル質が確認され、Ikkαのノックアウトマウスの前歯にSRが存在する事が確認された。一方Notch-Ikkαの関係は現在まで報告されていない。しかし我々は、NotchのリガンドであるJagged2のノックアウトで認められる口腔上皮の癒合とPalata1 Shelfのelevation不全による口蓋裂を、Ikkαのノックアウトマウスにおいても見出し、いくつかの組織においてIkkα-Notchが密接に関連している事が示唆された。以上の事より前歯の発生には、NF-kBの活性を促すIkkαと、それによるNotchの活性が重要であることが示唆された。

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  • ケモカインを介したヒト破骨細胞形成の制御機構の解明と歯周治療への応用の可能性

    研究課題/領域番号:16592077

    2004年 - 2005年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    岡松 良昌, 小林 誠, 宮澤 康, 大峡 淳, 滝口 尚

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    配分額:3600000円 ( 直接経費:3600000円 )

    破骨細胞は骨組織にのみ存在し、骨吸収を司る多核巨細胞である。これまで破骨細胞のユニークな特性に関して数多くの研究がなされてきたが、近年RANKL(receptor activator NF-kB ligand)-RANKシグナルの発見により、破骨細胞の分化・機能発現が分子レベルで説明されるようになってきた。しかしながら、生理的状態や炎症状態において破骨細胞前駆細胞が骨吸収の場に供給されるメカニズムに関する情報は少ない。ケモカインは好中球やリンパ球に対し走化性を示し、炎症反応や免疫応答で重要な役割を演じていると考えられている。しかし、破骨細胞におけるケモカインの役割は未だ不明な点が多く、骨芽細胞と破骨細胞前駆細胞におけるケモカインの旬括的な報告はほとんどない。そこで本研究では、破骨細胞前駆細胞の供給・遊走や破骨細胞形成の制御に関与するケモカインを網羅的に探査し、またそのケモカインの細胞内シグナル伝達経路を解明することから炎症性骨吸収を有する疾患に対する診断や治療への応用の可能性を検討する目的に行ってきた結果、現在までに以下のような結果を得た。
    1)マウス骨髄細胞由来の成熟破骨細胞はMIP-1gammaおよびCCR1遺伝子発現が優位に上昇していた。
    2)MIP-1gammaはNF-kBを介してシグナル伝達していることが明らかとなった。
    3)マウス骨髄細胞由来の成熟破骨細胞はintegrin beta7遺伝子発現が優位に上昇しており、MIP-1gammaはintegrin beta7遺伝子発現を上昇している可能性がRT-PCR法にて認められた。
    4)ヒト末梢血由来CD14陽性モノサイトをRANKLおよびM-CSFで刺激するとTRAP陽性多核巨細胞が認められた。またこれらの細胞はMIP-1alphaを産生している可能がELISA法で認められた。
    5)マウス頭蓋骨由来の骨芽細胞をIL-1で刺激すると、RANTESおよびMIP-1alphaの産生の上昇が認められた。
    今回の結果から、多様なケモカインが破骨細胞の分化誘導に関わっていると考えられた。今後これらのケモカインの作用を整理し、歯周病との関連性を調べて行く予定である。

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  • ヒト歯根膜細胞特異的な既知あるいは未知のフェノタイプマーカーの探索

    研究課題/領域番号:16592078

    2004年 - 2005年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    小林 誠, 村上 伸也, 宮澤 康, 大峡 淳, 岡松 良昌, 滝口 尚

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    配分額:3600000円 ( 直接経費:3600000円 )

    本研究では、ヒト歯根膜細胞特異的な既知あるいは未知のフェノタイプタイプマーカーを探索することを最終目的として、以下に示す研究成果を得た。
    培養ヒト歯根膜細胞における各種細胞マーカー分子の発現パターンとその継代による変化の検討:
    初代培養ヒト歯根膜細胞(HPDLC)における各種細胞マーカー陽性細胞率は、幹細胞マーカー;CD105,CD44,CD29、インテグリン;CD49c,CD49eは高く,一方インテグリン;CD49d,CD49f、造血幹細胞マーカー;CD117、神経幹細胞マーカー;AC133、造血系細胞マーカー;CD34,CD45は低く、またこれらの発現頻度の継代による顕著な変化は認められなかった。
    培養ヒト歯根膜細胞中における各種間葉系細胞前駆細胞の存在の確認:
    ヒト骨髄由来間葉系幹細胞(HBMSC)と同様にHPDLC中にも間葉系幹細胞マーカーを発現する細胞が多く存在していた。しかし、HPDLCはHBMSCと同等の骨分化誘導能(ALP・osteopontin発現の上昇,石灰化結節の誘導)を示したのに対して、脂肪細胞へ分化能(oll-red Oで染色される細胞の増加,LPL・PPARγ発現の上昇)は低く、軟骨細胞への分化(type II collagen発現の誘導)は認められなかった。したがって、HPDLC中には多数の骨芽細胞前駆細胞と少数の脂肪前駆細胞が存在するものの、軟骨前駆細胞は存在しないあるいは著しく少ないと考えられる。そこで、HPDLC中のALP低発現の細胞集団(ALP-HPDLC)を分取し、この細胞集団における多分化能を検討したところ、脂肪前駆細胞はむしろALP-HPDLCに多く存在していた。
    したがって、HPDLC中には、骨芽細胞様細胞が多数存在しているが、脂肪前駆細胞も少数存在しており、この脂肪前駆細胞はALP陰性の細胞集団に多く含まれていると考えられる。

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  • 歯根膜の組織特異性に関する基礎的研究

    研究課題/領域番号:09771646

    1997年 - 1998年

    制度名:科学研究費助成事業

    研究種目:奨励研究(A)

    提供機関:日本学術振興会

    大峡 淳

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    配分額:1900000円 ( 直接経費:1900000円 )

    歯根膜の組織特異性の有無を、外骨膜との比較により検索した。
    外骨膜、歯根膜、骨組織それぞれから得た細胞間でALPase活性やPTHによるcAMP産生などに違いは認められなかった。
    歯根膜を除去し、外骨膜をラッピングした歯根の顎骨肉への移植では、移植歯根表面への新生セメント質の形成は認められなかったものの、移舶歯根の骨性癒着もあまり観察されなかった。また外骨膜から得た細胞を培養した象牙質片の顎骨内への移植でも、同様の結果が認められた。
    また外骨膜および歯根膜それぞれを培養した象牙質片の移植後に発現する蛋白の検索においても、両者間に違いは認められなかった。
    今回の結果では、外骨膜には多数の骨芽細胞様細胞が含まれるものの、いずれの外骨膜応用群でも新生セメント貿は観察されなかった。一方、そのような多数の骨芽細胞様細胞が含まれるにもかかわらず、骨性癒着はほとんど観察されなかった。以上のことから、歯根膜という非石灰化組織の維持は歯根膜以外の組織でも可能であるのに対し、セメント質形成は歯根膜にのみ存在する特異的能力である可能性が高い事が示唆された。今後例数を増やし、さらに検索していく予定である。
    またこの石灰化抑制を検討する目的で、mineralized bone nodule形成能を利用した検索を、現在行っている。

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  • 歯槽骨再生に及ぼす歯根膜の関与に関する基礎的研究

    研究課題/領域番号:08771732

    1996年

    制度名:科学研究費助成事業

    研究種目:奨励研究(A)

    提供機関:日本学術振興会

    大峡 淳

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    配分額:900000円 ( 直接経費:900000円 )

    歯周病により破壊された骨欠損にGTR法を応用した場合、新生セメント質を伴う結合組織性付着の獲得はみられるものの、骨の再生は非常に少ないことが分かってきた。これに対して、インプラント周囲の骨欠損や歯槽堤形成術においてGBR法を応用した場合には、十分な骨再生がみられることが報告されている。両者間でこのような骨再生の違いかなる理由により生じるかについては、骨が再生するスペースや、骨欠損形態が関与するのではないかという報告があるがいまだ明確な答は得られていない。そこで我々は、歯周組織再生過程で歯根膜の存在の有無が歯槽骨の再生に影響を与えているのではないかという仮説を立て、その仮説を明確にすることを目的とした実験を考案して検討を進めてきた。
    その結果、犬を用いて歯根膜存在群と歯根膜除去群とのそれぞれの歯槽骨再生に対する影響を観察すると臨床所見並びにエックス線所見においては、一部の標本で歯根膜除去群が歯根膜存在群に比べて骨形成量の多い傾向が認められたが、ほとんどの標本では両群間で差は認められなかった。組織学的所見においては、いずれの犬においても歯根膜存在群では新生骨骨頂まで歯根膜の再生が認められたのに対し、歯根膜除去群では著名な歯根吸収ならびに歯根と歯槽骨とのアンキロ-シスが認められた。両群ともに分割歯根の歯冠側端まで新生骨の形成が認められ、両群間で差は認められなかった。また、免疫組織化学的検索においても両群間で差は認められなかった。
    歯根膜存在群、歯根膜除去群から新生肉芽組織を採取し、それらの生化学的検索およびDiffusion Chamberを用いたそれらの石灰化形成能の検索については、現在組織切片等の作成中である。
    現在までの結果より考察すると、歯根膜の存在は歯槽骨再生にあまり影響しない可能性のある事が考えられるが、進行中の実験も含め今後更なる検討を加える予定である。

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  • 歯根膜細胞の有無が歯槽骨再生に及ぼす影響についての基礎的研究

    研究課題/領域番号:07771783

    1995年

    制度名:科学研究費助成事業

    研究種目:奨励研究(A)

    提供機関:日本学術振興会

    大峡 淳

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    配分額:1000000円 ( 直接経費:1000000円 )

    歯周病の治癒に対する理想的な治癒形態は、歯周組織の再生であり、歯根膜組織由来及び歯槽骨由来の細胞が重要な役割を演じている。そこで近年それらを選択的に誘導するGTR法が考案されたが、骨の再生は非常に少ないことが明らかとなり、それに比べインプラントにおいてGTR法を応用した場合では十分な骨の再生が得られることが報告されている。これらの違いに対する明確な答は得られていないが、歯根膜由来細胞が骨芽細胞様細胞であるとする報告や歯根膜組織が正常な場合石灰化抑制因子を産生しているとの報告などがある。そこで今回、この歯根膜の存在の有無が、歯周組織再生特に歯槽骨の再生にどのような影響を及ぼすか、またその要因は何かを明確にすることを目的として実験を行った。
    成犬の前臼歯を抜歯し治癒させた後、他の前臼歯を歯根膜有り群、歯根膜無し群に分け、その抜歯窩治癒部に移植し、その頬側に骨欠損を作製した。その結果、歯根膜有り群と無し群との間で、骨欠損内でのセメント質及び歯槽骨の再生量に有為な差は認められなかった。その考察として、移植歯であってもsubmergeでGTR法を行った場合、今回採用した程度の大きさの骨欠損では両群とも良好に治癒し、歯根膜の有無の骨形成への影響が確認できなかったものと考えられた。そのため大幅に骨欠損を拡大し同様の実験を行ったところ両群間に差が認められたので、現在例数を増やしその再現性を確認している。それに並行して、その両群の骨欠損内に形成された新生肉芽組織の生化学的検索を行ったが、アルカリフォスファターゼ活性やtypeIコラーゲン量に若干の差が認められ、現在その再現性の確認を行っている。またその新生肉芽組織のラット膜腔内への移植を開始した。今後、両群からの新生肉芽組織の器官培養における培養上清中のPGE_2やMMP-1などの測定や、out growthさせた細胞のmineralized bone nodule形成能を検討していく予定である。

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