REST represses a subset of the pancreatic endocrine differentiation program.
REST represses a subset of the pancreatic endocrine differentiation program.
复制标题
REST压抑胰腺内分泌区分程序的子集。
DOI：
10.1016/j.ydbio.2015.07.002
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发表时间：
2015-09-15
影响因子：
2.7
通讯作者：
Grapin-Botton A
中科院分区：
文献类型：
--
作者：
Martin D;Kim YH;Sever D;Mao CA;Haefliger JA;Grapin-Botton A
为了有助于设计成功的β细胞分化策略来治愈1型糖尿病，我们试图通过研究转录抑制因子REST在发育中的胰腺中的作用来揭示限制内分泌命运获得的障碍。Rest表达在神经元和内分泌细胞中被阻止，这是它们正常功能所必需的。在发育过程中，REST抑制神经元分化程序中的一部分基因，而Rest随着神经元分化而下调。在这里，我们调查的作用，休息胰腺内分泌细胞的分化，这是分子上接近神经元。我们发现，休息是广泛表达的胰腺祖细胞，它是下调分化的内分泌细胞。REST在Pdx 1+祖细胞中的持续表达损害了内分泌定向的Neurog 3+祖细胞的分化，在E18.5前减少了β和α细胞群，并在成年期引发糖尿病。Pdx 1+祖细胞中Rest的条件性失活不足以触发内分泌分化，但上调了分化基因的子集。我们的研究结果表明，转录抑制因子REST在胰腺祖细胞中是活跃的，在胰腺祖细胞中，它控制了部分β细胞分化程序的激活。
To contribute to devise successful beta-cell differentiation strategies for the cure of Type 1 diabetes we sought to uncover barriers that restrict endocrine fate acquisition by studying the role of the transcriptional repressor REST in the developing pancreas. Rest expression is prevented in neurons and in endocrine cells, which is necessary for their normal function. During development, REST represses a subset of genes in the neuronal differentiation program and Rest is down-regulated as neurons differentiate. Here, we investigate the role of REST in the differentiation of pancreatic endocrine cells, which are molecularly close to neurons. We show that Rest is widely expressed in pancreas progenitors and that it is down-regulated in differentiated endocrine cells. Sustained expression of REST in Pdx1+ progenitors impairs the differentiation of endocrine-committed Neurog3+ progenitors, decreases beta and alpha cell mass by E18.5, and triggers diabetes in adulthood. Conditional inactivation of Rest in Pdx1+ progenitors is not sufficient to trigger endocrine differentiation but up-regulates a subset of differentiation genes. Our results show that the transcriptional repressor REST is active in pancreas progenitors where it gates the activation of part of the beta cell differentiation program.