Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3
Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3
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DOI：
10.1128/mcb.20.12.4445-4454.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Lemaigre, FP
中科院分区：
文献类型：
--
作者：
Jacquemin, P;Durviaux, SM;Lemaigre, FP
肝细胞核因子6(HNF-6)是一类新的同源异域转录因子的原型。在小鼠发育过程中，HNF-6在上皮细胞中表达，而上皮细胞是胰腺外分泌和内分泌细胞的前体。我们通过失活HNF-6基因在小鼠胰腺分化中的作用进行了研究。在HNF6(-/-)胚胎中，外分泌胰腺看起来正常，但内分泌细胞分化受损。神经原蛋白3(NGN-3)是一种决定内分泌细胞前体的转录因子，其表达几乎被取消。与此一致，我们证明了HNF-6与NGN3基因启动子结合并刺激。出生时，仅发现少量内分泌细胞，朗格汉斯胰岛缺失。之后，内分泌细胞数量增多，出现胰岛。然而，胰岛的结构受到干扰，其β细胞缺乏葡萄糖转运蛋白2的表达。成年HNF6(-/-)小鼠患有糖尿病。综上所述，我们的研究结果表明，HNF-6在胰腺的前体阶段控制着胰腺的内分泌分化，并确认HNF-6是胰腺中前内分泌基因NGN3的第一个正向调节因子。他们还表明，HNF-6是人类糖尿病的候选基因。
Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. We have investigated the role of HNF-6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6(-/-) embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin 3 (Ngn-3), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their beta cells were deficient in glucose transporter 2 expression. Adult hnf6(-/-) mice were diabetic. Taken together, our data demonstrate that HNF-6 controls pancreatic endocrine differentiation at the precursor stage and identify HNF-6 as the first positive regulator of the proendocrine gene ngn3 in the pancreas. They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans.