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

转录因子Foxl1在消化器官的间质中特异表达。我们建立了Foxl1基因敲除(KO)小鼠，发现Foxl1f的缺失会导致Oxynticeptic样细胞的分化，这种细胞同时具有分泌盐酸的壁细胞和分泌胃蛋白酶原的主细胞的特征，这些细胞只在低等脊椎动物的胃中存在，而在哺乳动物的胃中不存在。因此，在哺乳动物从爬行动物进化的过程中，Foxl1f的表达似乎在壁细胞和主细胞的分化过程中起着关键作用。为了阐明Foxl1f的作用机制，我们比较了KO小鼠和野生型(WT)小鼠胃肠组织中的基因表达谱，发现野生型(WT)和野生型(WT)小鼠胃肠组织中Synaxin3、VAMP2、Rab3a和ARF6蛋白的表达水平并不完全相同，KO小鼠SNAP25的表达水平也有所下降。KO壁细胞的酸分泌缺陷可能是SNAP25减少导致的小管小管和分泌小管之间的膜融合受损和H，K-ATPase质子排泄亚基表达减少的共同作用的结果。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的缺乏导致了EphB2和EphB2的异位和表达增加，这两种基因与它们的配体EPhinB1一起被证明参与了调节上皮细胞沿隐窝-绒毛轴的位置。此外，我们还检测到KO小鼠间充质中Wnt4、Wnt11和Glypican3的表达增加，上皮细胞中Syndecan2的表达增加。这些结果改变了细胞外基质的表达。

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.