Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice
Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice
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DOI：
10.1101/gad.11.18.2323
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发表时间：
1997-09-15
影响因子：
10.5
通讯作者：
Tsai, MJ
中科院分区：
文献类型：
--
作者：
Naya, FJ;Huang, HP;Tsai, MJ
已经使用胰岛素基因调控作为范例分离了参与胰腺内分泌发育的候选转录因子。在胰腺内分泌细胞、肠和脑中表达的细胞类型限制性碱性螺旋-环-螺旋（bHLH）基因BETA2/NeuroD激活胰岛素基因转录并可诱导神经元分化。为了理解BETA2在胰腺内分泌细胞分化中的重要性，通过基因靶向实验产生缺乏功能性BETA2基因的小鼠。携带BETA2基因靶向破坏的小鼠患上了严重的糖尿病，并在围产期死亡。纯合子BETA2缺失小鼠产生胰岛素的β细胞数量显著减少，并且未能发育成熟的胰岛。胰岛形态发生似乎在E14.5和E17.5之间被阻止，这是一个以β细胞群的主要扩增为特征的时期。这些小鼠中严重糖尿病的存在表明适当的胰岛结构在血糖稳态中起重要作用。此外，分泌素和胆囊收缩素生产肠内分泌细胞未能在BETA 2的情况下发展。这两种胰腺分泌素的缺乏可能解释了胰腺腺泡外分泌细胞极性异常和不能分泌酶原颗粒的原因。神经系统似乎正常发育，尽管在分化的神经元中有大量的BETA 2表达。因此，BETA 2对于由肠道内胚层产生的几种特化细胞类型的正常发育至关重要。
Candidate transcription factors involved in pancreatic endocrine development have been isolated using insulin gene regulation as a paradigm. The cell-type restricted basic helix-loop-helix (bHLH) gene, BETA2/NeuroD, expressed in pancreatic endocrine cells, the intestine, and the brain, activates insulin gene transcription and can induce neurons to differentiate. To understand the importance of BETA2 in pancreatic endocrine cell differentiation, mice lacking a functional BETA2 gene were generated by gene targeting experiments. Mice carrying a targeted disruption of the BETA2 gene developed severe diabetes and died perinatally. Homozygous BETA2 null mice had a striking reduction in the number of insulin-producing beta cells and failed to develop mature islets. Islet morphogenesis appeared to be arrested between E14.5 and E17.5, a period characterized by major expansion of the beta cell population. The presence of severe diabetes in these mice suggests that proper islet structure plays an important role in blood glucose homeostasis. In addition, secretin-and cholecystokinin-producing enteroendocrine cells failed to develop in the absence of BETA2. The absence of these two pancreatic secretagogs may explain the abnormal cellular polarity and inability to secrete zymogen granules in pancreatic acinar exocrine cells. The nervous system appeared to develop normally, despite abundant expression of BETA2 in differentiating neurons. Thus, BETA2 is critical for the normal development of several specialized cell types arising from the gut endoderm.