祖细胞
PDX1型
Wnt信号通路
胰腺
细胞生物学
祖细胞
生物
内分泌系统
Notch信号通路
内分泌学
肠内分泌细胞
内科学
干细胞
小岛
癌症研究
胰岛素
医学
信号转导
激素
作者
Jian Sun,Yanqiu Wang,Hui Fu,Fuyun Kang,Jiaxi Song,Mingqing Xu,Guang Ning,Jian Wang,Weiqing Wang,Qidi Wang
出处
期刊:Diabetes
[American Diabetes Association]
日期:2023-11-14
被引量:1
摘要
The important role of m6A RNA modification on β cell function has been established, yet how it regulates pancreas development and endocrine differentiation remains unknown. Here, we generated transgenic mice lacking RNA methyltransferase-like 3 (Mettl3) specifically in Pdx1+ pancreatic progenitor cells and found the mutant mice developed hyperglycemia and hypo-insulinemia at 2 weeks of age, with atrophic pancreas, reduced islet mass and abnormal increase in duct formation. At E15.5, Mettl3 deletion caused a significant loss of Ngn3+ endocrine progenitor cells, which was accompanied by increased Sox9+ duct precursor cells. We identified histone deacetylase 1(Hdac1) as the critical direct m6A target in bipotent progenitor, whose degeneration caused abnormal activation of Wnt/Notch signaling pathway and blocked endocrine differentiation. This transformation could be manipulated in embryonic pancreas culture in vitro through the regulation of the axis of Mettl3-Hdac1-Wnt/Notch signaling. Our finding that Mettl3 determines endocrine lineage through modulating Hdac1 activity during the transition of bipotent progenitor might help in the development of targeted endocrine cell protocols for diabetes treatment.
科研通智能强力驱动
Strongly Powered by AbleSci AI