Elucidation of the function of retinoic acid signaling contributed to midfacial defects

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K19290
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57070:Developmental dentistry-related
• Research Institution: Osaka University
• Principal Investigator: Ohara Haruka 大阪大学, 歯学部附属病院, 医員 (40754726)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 正中顔面裂 / レチノイン酸シグナル / Rdh10 / 歯科矯正

Outline of Final Research Achievements

We showed that Rdh10 loss-of-function leads to a substantial reduction in RA signaling in the developing frontonasal process during early embryogenesis, which results in a variety of craniofacial anomalies, including midfacial cleft and agenesis of upper incisors. Elevated apoptosis in post-migratory cranial neural crest cells and a substantial reduction of Alx1 and Alx3 transcription in the developing frontonasal process are associated with midfacial cleft in Rdh10-deficient mice. Importantly, expanded Shh signaling in the ventral forebrain, as well as partial abrogation of midfacial defects in Rdh10 mutants via inhibition of Hh signaling, indicates that misregulation of Shh signaling underlies the pathogenesis of reduced RA signaling associated midfacial defects. These data illustrate the spatiotemporal function of Rdh10 and RA signaling during early embryogenesis and their importance in orchestrating molecular and cellular events essential for normal midfacial development.

Free Research Field

歯科矯正学

Academic Significance and Societal Importance of the Research Achievements

異常な顔面突起の成長や癒合、骨形成の異常は、顎顔面形成不全の原因となり、口唇口蓋裂は顎顔面領域において高頻度で生じる先天性疾患である。Rdh10遺伝子が制御する顎顔面領域のRAシグナルが顔面正中部の癒合における分子基盤であることが示唆されることに着目し、本研究ではRdh10遺伝子を機能阻害したマウスの形態や組織学的表現型を詳細に解析し、正中顔面裂および切歯の形成異常の発症に関連するRAシグナルの機能解明を行った。本研究によりRAシグナル異常により誘発される顎顔面形成異常に関する基礎的な理解が深まり、予防法や治療法の確立に貢献することが期待できる。