Identification of genetic factors act on heterogeneous pathology in microphthalmia using rat model

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K06473
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Tokyo University of Agriculture
• Principal Investigator: Wada Kenta 東京農業大学, 生物産業学部, 教授 (20508113)
• Co-Investigator(Kenkyū-buntansha): 吉川 欣亮 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, プロジェクトリーダー (20280787)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: ラット / 小眼球症 / 眼球発生

Outline of Final Research Achievements

NAK/Nokh (NAK) rats exhibit microphthalmia with heterogeneous pathology like humans and we identified that it was caused by genetic background and maternal effects. We revealed that a large deletion mutation of Cyp4v3 gene leads to reduction of its transcript and its homozygous mutation was significantly correlated to development of anophthalmia. In addition, we suggested that hypoplasia of the eyes in NAK rats was caused by loss of neural retina but not retinal pigment epithelium during eye development through several marker study. Finally, we generated genome-editing mice targeting Cyp4v3 gene and investigated its eye phenotypes. Unexpectedly, Cyp4v3 genome-editing mice did not show any defects of eye development. These results suggested that microphthalmia of NAK rats was influenced by other factor besides mutation of Cyp4v3. Alternatively, we predicted that normal eye development of Cyp4v3 genome-editing mice might be caused by species differences between mouse and rat.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

本研究は、その発症メカニズムが不明である小眼球症における病態の不均一性を再現するラット系統を対象としている。本研究に成果は、ヒト小眼球症の原因遺伝子、発症メカニズム、ならびに病態の不均一性を引き起こす遺伝的要因の解明に貢献する情報となることが予測される。また、眼球発生のプロセスは未だ不明な点も残している。従って、NAKにおいて観察された神経網膜の消失は、そのメカニズムと、水晶体発生との関連を明らかにするためのモデルになることも期待できる。