The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity
The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity
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DOI：
10.1016/j.ydbio.2003.12.008
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发表时间：
2004-04-01
影响因子：
2.7
通讯作者：
Serup, P
中科院分区：
文献类型：
--
作者：
Heller, RS;Stoffers, DA;Serup, P
Brain 4（Bm 4/Pou 3f 4）和Pax 6分别是POU同源结构域和配对同源结构域转录因子，它们在大脑和胰腺中表达-g-lucagon的细胞中表达。brn 4的表达开始于胚胎第10天的胰腺，就在pax 6之前，两者都出现在胰高血糖素免疫反应细胞中。在稍后的时间点，E19，没有观察到Brn 4与胰岛素或生长抑素的共定位，但是可以发现罕见的胰腺多肽（PP）产生细胞，而Pax 6在所有内分泌细胞中发现。这些数据表明，brn 4是唯一的a细胞特异性转录因子尚未确定，因此，我们试图分析a细胞的发展和功能，在小鼠与brn 4基因的靶向中断。在纯合子brn 4（-/-）小鼠中，胰腺芽形成、胰高血糖素细胞数量和生理测量均正常。在胰高血糖素细胞中发现的其他转录因子的检查显示正常Pax 6和Nkx2.2免疫反应性，表明Brn 4不调节这些转录因子。Pax 6突变小鼠（pax 6（Sey/Sey）），在pax 6中具有天然失活突变，具有很少的内分泌细胞，但正常数量的Brn 4和Nkx2.2细胞。pax 6突变体的胰腺表型可以用含有人Pax 6基因的YAC克隆来挽救。(C)2004年爱思唯尔公司All rights reserved.
Brain 4 (Bm4/Pou3f4) and Pax6 are POU-homeodomain and paired-homendomain transcription factors, respectively, that are expressed in the brain and the -g-lucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic day 10 in the pancreas, just before pax6 and both appear in the glucagon immunoreactive cells. At a later time point, E19, no Brn4 co-localization is observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)-producing cell can be found, while Pax6 is found in all endocrine cells. These data suggest that brn4 is the only a-cell specific transcription factor yet identified; therefore, we sought to analyze a-cell development and function in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-) mice, pancreatic bud formation, glucagon cell numbers and physiological measurements all appear normal. Examination of other transcription factors found in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting that Brn4 does not regulate these transcription factors. Pax6 mutant mice (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene. (C) 2004 Elsevier Inc. All rights reserved.