INSULIN-PROMOTER-FACTOR-1 IS REQUIRED FOR PANCREAS DEVELOPMENT IN MICE
INSULIN-PROMOTER-FACTOR-1 IS REQUIRED FOR PANCREAS DEVELOPMENT IN MICE
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DOI：
10.1038/371606a0
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发表时间：
1994-10-13
期刊：
影响因子：
64.8
通讯作者：
EDLUND, H
中科院分区：
文献类型：
--
作者：
JONSSON, J;CARLSSON, L;EDLUND, H
哺乳动物的胰腺是一种混合的外分泌腺和内分泌腺，在大多数物种中，它起源于腹芽和背芽，随后合并形成胰腺。在小鼠和大鼠中，背侧胰腺形态发生的第一个组织学标志是在22-25体节期左右，十二指肠在肝脏水平上的背侧外翻，此后不久，腹侧外翻作为肝憩室的衍生物出现（1-3）。低水平的胰岛素基因转录本已经存在，并局限于背侧前肠内胚层的20体节，表明胰腺或胰岛素基因特异性转录因子在形态发生开始之前就存在于该区域（4）。胰岛素启动子因子1（IPF 1）是一种同源结构域蛋白，在成年小鼠胰腺中，其在β细胞中选择性表达，并结合并反式激活胰岛素启动子（5）。在小鼠胚胎中，IPF 1的表达仅限于发育中的胰腺原基，并在前肠内胚层被定向为胰腺命运时启动（5）。我们现在表明，Ipf 1基因中靶向突变的纯合子小鼠选择性地缺乏胰腺。突变的幼崽在胎儿发育中存活下来，但在出生后几天内死亡。胃肠道部分和所有其他内脏器官外观正常。在突变胚胎和新生儿中未检测到胰腺组织和胰岛素或胰淀粉酶的异位表达。这些发现表明，IPF 1是胰腺形成所必需的，并表明它起着决定普通胰腺前体细胞命运和/或调节其增殖的作用。
THE mammalian pancreas is a mixed exocrine and endocrine gland that, in most species, arises from ventral and dorsal buds which subsequently merge to form the pancreas. In both mouse and rat the first histological sign of morphogenesis of the dorsal pancreas is a dorsal evagination of the duodenum ai the level of the liver at around the 22-25-somite stage, and shortly thereafter a ventral evagination appears as a derivative of the liver diverticulum(1-3). Low levels of insulin gene transcripts are already present and restricted to the dorsal foregut endoderm at 20 somites, suggesting that pancreas- or insulin gene-specific transcriptional factors are present in this region before the onset of morphogenesis(4). Insulin-promoter-factor 1 (IPF1) is a homeodomain protein which, in the adult mouse pancreas, is selectively expressed in the beta-cells and binds to and transactivates the insulin promoter(5). In mouse embryos, IPF1 expression is restricted to the developing pancreatic anlagen and is initiated when the foregut endoderm is committed to a pancreatic fate(5). We now show that mice homozygous for a targeted mutation in the Ipf1 gene selectively lack a pancreas. The mutant pups survive fetal development but die within a few days after birth. The gastrointestinal part and all other internal organs were normal in appearance. No pancreatic tissue and no ectopic expression of insulin or pancreatic amylase could be detected in mutant embryos and neonates. These findings show that IPF1 is needed for the formation of the pancreas and suggest that it acts to determine the fate of common pancreatic precursor cells and/or to regulate their propagation.