Roles of Foxc1/2 in nephron development

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08735
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tokai University
• Principal Investigator: Motojima Masaru 東海大学, 医学部, 准教授 (80468636)
• Co-Investigator(Kenkyū-buntansha): 松阪 泰二 東海大学, 医学部, 教授 (50317749)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ネフロン発生 / エリスロポエチン産生細胞 / 腎間質前駆細胞 / Foxc1 / Foxc2

Outline of Final Research Achievements

Nephron development proceeds with reciprocal interactions among three layers: nephron progenitors (NPs), stromal progenitors (SPs), and ureteric buds. We found Foxc1 and Foxc2 (Foxc1/2) expression in NPs and SPs. Systemic deletion of Foxc1/2 at E13.5 resulted in ectopic epithelialization of NPs and anemia. NP-specific deletion did not cause these phenotypes, indicating that Foxc1/2 in SPs contributed to the maintenance of NPs and differentiation of stromal erythropoietin-producing cells. Single-cell RNA-seq analysis indicated transformation of some NPs to vascular endothelial cells, reduced numbers of self-renewing NP and SP populations, downregulation of crucial genes for kidney development, and upregulation of genes that were not usually expressed in NPs and SPs. Thus, Foxc1/2 maintains NPs and SPs by regulating the expression of multiple genes.

Free Research Field

発生、分子生物学、腎臓病学

Academic Significance and Societal Importance of the Research Achievements

Foxc1とFoxc2（Foxc1/2）は、腎発生に必須の転写因子であることは知られていたが詳細は不明であった。本研究により、Foxc1/2がネフロン前駆細胞とその周囲の腎間質前駆細胞の分化を制御していることが明らかになった。シングルセルRNA-seq解析により、それぞれの分化経路やFoxc1/2によって発現調節される遺伝子も判明した。これらの研究成果は腎再生や腎治療への応用が期待される。