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mecanism of Diffrentiation and Evolution of Parietal and Chief Cells in Vertebrate Stomachs

脊椎动物胃壁细胞和主细胞的分化和进化机制

基本信息

批准号：
14540611
负责人：
FUKAMACHI Hiroshi
金额：
$ 2.3万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14540611/
关键词：
Fkh5 gene Foxl1 gene Stomach Intestine Epithelial-mesenchymal interaction Extracellular Matric Eph Wnt EphB プロテオグリカン

项目摘要

The transcription factor Foxl1 is specifically expressed in the mesenchyme of digestive organs. We generated Foxl1 knockout (KO) mice and found that loss oFoxl1f led to differentiation of oxynticopeptic-like cells which have features of both hydrochloric acid-secreting parietal and pepsinogen-secreting chief cells, and which are only found in stomachs of lower vertebrates but not in those of mammals. Thus expression oFoxl1f seems to play a key role in the differentiation of parietal and chief cells during evolution of mammals from reptiles. To elucidate the mechanism of action oFoxl1f, the gene expression profiles in KO and wild type(WT) gastro-intestinal tissues were compared.We found that the expression level of syntaxin3, VAMP2, Rab3a and ARF6 proteins was not almost equivalent between WT and KO mic, shereas that of SNAP25 decreased in KO mice. Defect in acid secretion from KO parietal cells seems to result form the combined effect of the impairment in membrane fusion between tubulovesicles and secretory canaliculi due to reduced SNAP25 and a decrease in the expression of H, K-ATPase subunits for proton excretion.The epithelial hyperplasias are found both in gastric and intestinal tissues in KI mice. Thus gene expression profiles were also compared in intestinal tissues. We found that in fully differentiated as well as developing small intestine, lack of fff resulted in ectopic and increased expression of EphB2 and EphB2, which, in collaboration with their ligand EphrinB1, have been demonstrated to be involved in regulating epithelial cell positioning along the crypt-villus axis. Furthermore, we detected an increase in Wnt4, Wnt11 and Glypican3 in mesenchyme, and an increase of Syndecan2 in epithelia of KO mice. These results altered expression of extracellular matrixes.

转录因子Foxl1在消化器官的间充质中特异性表达。我们培育了 Foxl1 敲除 (KO) 小鼠，发现 oFoxl1f 的缺失会导致泌酸肽样细胞分化，这些细胞具有分泌盐酸的壁层主细胞和分泌胃蛋白酶原的主细胞的特征，并且仅在低等脊椎动物的胃中发现，但在哺乳动物的胃中不存在。因此，oFoxl1f 的表达似乎在哺乳动物从爬行动物进化过程中壁细胞和主细胞的分化中发挥关键作用。为了阐明oFoxl1f的作用机制，我们比较了KO和野生型（WT）胃肠组织中的基因表达谱。我们发现WT和KO小鼠之间的syntaxin3、VAMP2、Rab3a和ARF6蛋白的表达水平几乎不相等，并且KO小鼠中SNAP25的表达水平降低。 KO壁细胞的酸分泌缺陷似乎是由于SNAP25减少和H，K-ATP酶亚基表达减少导致质子排泄的小管泡和分泌小管之间膜融合受损的综合作用所致。KI小鼠的胃和肠组织中均发现上皮增生。因此，还比较了肠道组织中的基因表达谱。我们发现，在完全分化和发育的小肠中，fff 的缺乏导致 EphB2 和 EphB2 的异位表达和表达增加，EphB2 与其配体 EphrinB1 合作，已被证明参与调节上皮细胞沿隐窝绒毛轴的定位。此外，我们检测到 KO 小鼠间充质中 Wnt4、Wnt11 和 Glypican3 的增加，以及上皮细胞中 Syndecan2 的增加。这些结果改变了细胞外基质的表达。