NKX6 transcription factor activity is required for α- and β-cell development in the pancreas
NKX6 transcription factor activity is required for α- and β-cell development in the pancreas
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DOI：
10.1242/dev.01875
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发表时间：
2005-07-01
期刊：
影响因子：
4.6
通讯作者：
Sander, M
中科院分区：
文献类型：
--
作者：
Henseleit, KD;Nellson, SB;Sander, M
在糖尿病个体中，葡萄糖稳态的失衡是由胰岛的胰岛素分泌β细胞的损失或功能障碍引起的。由于在体外成功产生胰岛素产生细胞可以治愈糖尿病，最近的研究已经探索了β细胞形成的分子程序。从这些研究中，同源结构域转录因子NKX6.1已被证明是一个关键的球员。在Nkx6.1突变体中，β细胞数量选择性减少，而其他胰岛细胞类型正常发育。然而，NKX6.1下游的分子事件以及在NKX6.1不存在的情况下确保残留β细胞形成的分子途径在很大程度上是未知的。在这里，我们发现Nkx6.1蛋白，Nkx6.2，在胰腺发育过程中表达，并部分补偿NKX6.1功能。令人惊讶的是，我们对Nkx6化合物突变小鼠的分析揭示了以前未被认识到的α细胞形成中对NKX6活性的要求。这一发现表明NKX6因子在内分泌细胞分化中的作用比以前提出的更普遍。与NKX6因子类似，转录因子MYT1最近被证明可以调节α细胞和β细胞的发育。我们证明了Myt 1的表达依赖于Nkx6基因的总剂量，因此确定Myt 1作为内分泌分化途径中Nkx6基因的可能下游靶点。
In diabetic individuals, the imbalance in glucose homeostasis is caused by loss or dysfunction of insulin-secreting beta-cells of the pancreatic islets. As successful generation of insulin-producing cells in vitro could constitute a cure for diabetes, recent studies have explored the molecular program that underlies beta-cell formation. From these studies, the homeodomain transcription factor NKX6.1 has proven to be a key player. In Nkx6.1 mutants, beta-cell numbers are selectively reduced, while other islet cell types develop normally. However, the molecular events downstream of NKX6.1, as well as the molecular pathways that ensure residual beta-cell formation in the absence of NKX6.1 are largely unknown. Here, we show that the Nkx6.1 paralog, Nkx6.2, is expressed during pancreas development and partially compensates for NKX6.1 function. Surprisingly, our analysis of Nkx6 compound mutant mice revealed a previously unrecognized requirement for NKX6 activity in alpha-cell formation. This finding suggests a more general role for NKX6 factors in endocrine cell differentiation than formerly suggested. Similar to NKX6 factors, the transcription factor MYT1 has recently been shown to regulate alpha- as well as beta-cell development. We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway.