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Role of Hedgehog Signaling on the differentiation of pancreas and pancreatic beta-cell function

Hedgehog 信号传导对胰腺分化和胰腺 β 细胞功能的作用

基本信息

批准号：
18591003
负责人：
WATADA Hirotaka
金额：
$ 2.57万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591003/
关键词：
Islet Insulin Hedgehog Ptc Type 2 Diabetes パッチド膵発生シグナル

项目摘要

Aim/hypothesis. Ectopic activation of hedgehog (Hh) signaling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analyzed the dose-dependent requirement of Patched (Ptc)1, a negative regulator of Hh signaling on pancreatic development.Methods. A recessive spontaneous mutant mouse, mesenchymal dysplasia (mes) express a mutated Ptcl, resulting in deletion of the most carboxy-terminal cytoplasmic domain of the Ptcl protein. In this study, we analyzed pancreatic morphology in Ptc1^+/+, Ptc1^+/mes, Ptc1^mes/mes., and Ptc1^/mes mouse embryos, as well as the islet mass in adult Ptc1^+/+, Ptc1^+/mes, and Ptc1^+1- mice.Results. Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in each Ptc1 mutant. The expression patterns of Pdx1, glucagon, insulin were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptcl mutant mice. The beta-, alpha-, and exocrine-cell masses decreased at E18.5 in parallel with increased Hh signaling. Among these, the beta cell mass showed the highest sensitively to Hh signaling with a significant decrease even in Ptc1^+1mes, mice. Adult Ptc1^+1- mice also showed a significant decrease in beta cell mass compared to wild-type mice.Conclusions/interpretation. Our findings indicate that the carboxy-terminal domain of Ptc1 is essential for pancreatic development. In addition, the loss of Ptc1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in Hh signaling.

目的/假设。Hhedgehog(HH)信号在胰腺中的异位激活诱导了胰腺中各种异常的形态发生事件。本研究分析了胰腺发育过程中HH信号的负调控因子Patted(PTC)1的剂量依赖性需求。一种隐性自发突变小鼠，间充质发育不良(MES)表达突变的PTCL，导致PTCL蛋白的大部分羧基末端胞质结构域的缺失。在本研究中，我们分析了Ptc1^+/+、Ptc1^+/Mes、Ptc1^Mes/Mes和Ptc1^/Mes小鼠胚胎的胰腺形态，以及成年Ptc1^+/+、Ptc1^+/Mes和Ptc1^+1-小鼠的胰岛质量。直到胚胎第12.5天，各Ptc1突变体均未发现明显的胰腺异常。Pdx1、胰升糖素、胰岛素的表达模式在所研究的小鼠之间也没有明显的差异。此后，PTCL突变小鼠出现了形态异常。在E18.5，随着HH信号的增加，β、α和外分泌细胞团减少。其中，β细胞团对HH信号的敏感度最高，即使在Ptc1^+1MES，小鼠的β细胞团也显著减少。与野生型小鼠相比，成年Ptc1^+1-小鼠的β细胞质量也显著减少。我们的发现表明，Ptc1的羧基末端结构域对于胰腺的发育是必不可少的。此外，Ptc1功能的丧失以剂量依赖的方式减少内分泌和外分泌细胞质量，其中β细胞对HH信号的变化特别敏感。