FCoR-Foxo1 Axis Regulates alpha-cell and beta-cell identity

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08988
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Keio University
• Principal Investigator: Kodani Noriko 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (50625332)
• Co-Investigator(Kenkyū-buntansha): 中江 淳 国際医療福祉大学, 医学部, 教授 (00344573)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: Pancreatic islets / Transcription factor / DNA methylation

Outline of Final Research Achievements

Pancreatic endocrine cell development into differentiated a- and b-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of a- and b-cell masses remain unclear. We have previously shown that Foxo1 CoRepressor (FCoR) inhibits Foxo1 activity by acetylation. Here we show that FCoR regulates the master a-cell regulatory transcription factor, Aristaless related homeobox (Arx), by DNA methylation and controls a-cell mass from the embryonic phase. FcorKO mouse exhibited b-to-a-cell conversion, suggesting that FCoR is also required to maintain b-cell. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic a-cell and b-cell identity.

Free Research Field

Diabetes, endocrinology and metabolism

Academic Significance and Societal Importance of the Research Achievements

膵内分泌前駆細胞が膵α細胞およびβ細胞へ分化を遂げる過程は厳密にコントロールされており、多くの転写因子が関与する。Foxo1は様々なインスリン感受性臓器において非常に多くの遺伝子の転写活性を制御する。これを可能にしているのが臓器毎に働くFoxo1結合タンパク質であり、FCoRは膵島においてFoxo1結合蛋白として同定された初めてのタンパク質である。したがって、FCoR－Foxo1 axisによる糖代謝の機能解析を行うことにより、糖代謝機構を明らかにしていくことで、糖尿病の病態解明につながる新たな知見を得ることができると考える。