2021 Fiscal Year Final Research Report
Expression characteristics of Sez12 gene, the murine homolog of DGCR2, in chondrocytes from 22q11.2 deletion syndrome model with knocked-in GFP
| Project/Area Number |
19K10062
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 57010:Oral biological science-related
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| Research Institution | Tokai University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
木村 穣 東海大学, 総合医学研究所, 特任教授 (10146706)
内堀 雅博 東海大学, 医学部, 助教 (50749273)
太田 嘉英 東海大学, 医学部, 教授 (60233152)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 22q11.2欠失症候群 / DGCR2 / Sez12 / Df1 / GFPノックイン / 肥大軟骨細胞 / 頭蓋底軟骨結合 / TGF-betaシグナル |
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| Outline of Final Research Achievements |
To explore the DGCR2 gene function, we generated Sez12 (the mouse homolog of DGCR2) -knockout/GFP-knocked-in mice, which showed maxillofacial hypoplasia caused by early malformations of basilar cartilage and differentiation defects of pre-hypertrophic chondrocytes. In the homozygous Sez12-KO chondrocytes treated with TGF-beta, we found significant activation of TGF-beta signaling and decrease of chondrocytes with expression of type X collagen, compared to wild-type ones showing expression of both type II and type X collagen. Furthermore, the primary chondrocytes with heterozygous mutants from both Sez12-KO and Df1 region which is heterozygously deleted a large portion of mouse genome corresponding to human 22q11.2 showed similar maxillofacial phenotypes and knocked-in GFP expression. These results suggest that DGCR2 together with other gene(s) in 22q11.2 could regulate the TGF-beta signaling activity for differentiation from replicative chondrocytes to hypertrophic ones after birth.
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| Free Research Field |
口腔解剖学・口腔発生学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、ヒト染色体22番長腕11.2領域の欠失により引き起こされる顔貌異常の発症メカニズム解明のため、欠失ゲノム領域の遺伝子機能を検討し、22q11.2欠失症候群の顔貌骨格異常の根本的治療の基盤となった。本研究で解析されたDGCR2遺伝子は、22q11.2欠失領域のいくつかの遺伝子と協調して頭蓋底の軟骨内骨化に寄与している。特記すべきことは、DGCR2欠失マウスが生後若齢で顔貌異常を認めることである。つまり、本疾患のみならず、他の原因による顔面骨格異常であっても、DGCR2を標的とした出生後の活性調節治療で症状が改善できる可能性が示唆され、外科治療に依存しない出生後治療に期待がもてる。
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