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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proendocrine genes coordinate the pancreatic islet differentiation program in vitro.
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Proendocrine genes coordinate the pancreatic islet differentiation program in vitro.

机译：前内分泌基因在体外协调胰岛分化程序。

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摘要

In the developing pancreas, the basic helix-loop-helix (bHLH) protein Neurogenin3 (Ngn3) specifies which precursor cells ultimately will become endocrine cells and initiates the islet differentiation program. NeuroD1, a closely related bHLH protein and a downstream target of Ngn3, maintains the differentiation program initiated by Ngn3. We have developed an in vitro model of Ngn3-dependent differentiation by infecting pancreatic duct cell lines with an Ngn3-expressing adenovirus. We found that both Ngn3 and its downstream target NeuroD1 activated the islet differentiation program in these cells by inducing the expression of genes with early roles in the differentiation cascade, as well as genes characteristic of fully differentiated islet cells. Induction of these genes, as exemplified by the insulin1 gene, involved alteration of the local chromatin structure. Interestingly, the subsets of genes activated by Ngn3 and NeuroD1 were not completely overlapping, indicating that these two bHLH proteins servespecific functions in the development of the endocrine pancreas. In addition, microarray gene expression analysis identified a previously uncharacterized group of Ngn3-induced genes with potentially important roles in islet development and function. These studies demonstrate how Ngn3 initiates islet differentiation and provide us with a model for testing methods for producing islet cells for people with diabetes.
机译：在发育中的胰腺中，基本的螺旋-环-螺旋（bHLH）蛋白Neurogenin3（Ngn3）指定哪些前体细胞最终将变为内分泌细胞并启动胰岛分化程序。 NeuroD1是密切相关的bHLH蛋白，是Ngn3的下游靶标，它维持由Ngn3启动的分化程序。我们通过用表达Ngn3的腺病毒感染胰管细胞系，开发了Ngn3依赖性分化的体外模型。我们发现，Ngn3及其下游靶标NeuroD1都通过诱导在分化级联中具有早期作用的基因以及完全分化的胰岛细胞特征基因的表达，激活了这些细胞中的胰岛分化程序。这些基因的诱导，以胰岛素1基因为例，涉及局部染色质结构的改变。有趣的是，被Ngn3和NeuroD1激活的基因的子集并不完全重叠，这表明这两种bHLH蛋白在内分泌胰腺的发育中起着特定的作用。此外，微阵列基因表达分析确定了先前未鉴定的一组Ngn3诱导的基因，这些基因在胰岛发育和功能中可能具有重要作用。这些研究证明了Ngn3如何启动胰岛分化，并为我们提供了一种测试糖尿病人胰岛细胞产生方法的模型。

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