2022 Fiscal Year Final Research Report

Stage-specific Foxc2+ mesenchymal cells differentiation of the aortic segment in Foxc2 CreERT2 mice

Research Project

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Project/Area Number	17K10063
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Pediatrics
Research Institution	Tokyo Women's Medical University
Principal Investigator	Morishima Masae 東京女子医科大学, 医学部, 助教 (00241068)
Co-Investigator(Kenkyū-buntansha)	森川俊一東京女子医科大学, 医学部, 講師 (70339000) 北原秀治東京女子医科大学, 医学部, 特任准教授 (40510235) 清水一彦帝京大学, 医療技術学部, 教授 (90385394)
Project Period (FY)	2017-04-01 – 2023-03-31
Keywords	Foxc2遺伝子 / 心大血管発生 / 先天性疾患 / 鰓弓動脈（咽頭弓動脈） / 間葉系細胞 / 遺伝子改変マウス / 細胞系譜
Outline of Final Research Achievements	We examined the relationship between specific stage of the pharyngeal arch artery remodeling and the arterial media in the Foxc2-CreERT2; R26R-LacZ mice. Pregnant female Foxc2+/-; R26R mice mated with a Foxc2-CreERT2; R26R-LacZ male were given Tamoxifen (TAM, 75 mg/kg BW, i.p.) once during the organogenesis stage. Mutant fetuses were stained with X-gal at E18.5. Fetuses treated with TAM at E10.5 or E11.5 had pachycromatic and localized signals in the aortic arch and ductus. In pharyngeal arch tissue from Foxc2 null embryos, Foxc1 gene expression showed widely variation between individuals. These results suggest that the Foxc2+ mesenchymal cells may different stage-specifically to each segment, and one of the factors for the spectrum of the aortic arch anomalies under Foxc2 deficiency may be Foxc1 dosage.
Free Research Field	循環器発生学・心形態学
Academic Significance and Societal Importance of the Research Achievements	FOXC2 遺伝子はリンパ浮腫を伴う症候群の原因遺伝子とされるが、日本では心血管奇形例の報告がない。Foxc2ノックアウトマウスを129xBlack Swiss交雑種、ICR、C57BL/6Jの系統に戻し交配し、本遺伝子欠失時の大血管奇形に系統差があることを見出したが、要因が不明であった。今回、Foxc2-CreERT2マウスを用いて、間葉系細胞の遊走時差と、本遺伝子欠失時のFoxc1遺伝子の発現量変動が示され、遺伝的背景に関連する要因が示唆された。これは先天性疾患の人種差、個体差などと通じる可能性があり、さらなる検討が必要と考えられる。