2021/10/20 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

  • 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  

    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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  • 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   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   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   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  

    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.

    DOI: 10.1111/joa.13096

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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  

    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  

    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.

    DOI: 10.1016/j.gep.2019.04.002

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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  

    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  

    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.

    DOI: 10.1111/cge.13519

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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  

    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  

    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.

    DOI: 10.1002/dvdy.10

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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  

    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.

    DOI: 10.1016/j.neulet.2017.12.051

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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  

    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  

    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.

    DOI: 10.1371/journal.pone.0204126

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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  

    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  

    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.

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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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  • 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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  • 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.

    DOI: 10.1111/joa.12426

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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.

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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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  • 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  

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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.

    DOI: 10.1002/dvdy.24124

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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.

    DOI: 10.2330/joralbiosci.51.193

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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

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  • 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.

    DOI: 10.1177/154405910408300702

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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.

    DOI: 10.1177/154405910408300311

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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

  • 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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  • 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

  • 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

    基盤研究(B) 

    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 )

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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

    挑戦的研究(萌芽) 

    大峡 淳(代表者)

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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

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    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

    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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  • 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

    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

    挑戦的萌芽研究 

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    機関名:新潟大学

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