Lgr4基因在肠自稳态维持及肠炎中的功能研究
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摘要
Wnt信号通路在肠上皮细胞的增殖与分化过程中起着重要的调控作用,Lgr4作为一个经典的七次跨膜蛋白,是新鉴定出来的Rspondin蛋白家族的受体之一,并能够激活Wnt信号通路。但是Lgr4在动物体内是如何通过Wnt信号通路调节肠上皮的自稳态维持目前仍然不清楚。利用gene-trap小鼠模型,我们发现Lgr4主要在肠上皮隐窝中表达并且在小肠隐窝底部潘氏细胞(Paneth细胞)中表达较高。通过对Lgr4基因敲除小鼠肠组织学分析发现其Paneth细胞及Lgr5肠干细胞数目大大减少,Bmil肠干细胞数目也显著降低了。利用DSS诱导肠炎性疾病(Inflammatory bowel diseas)模型,Lgr4基因敲除鼠相对于野生型小鼠表现出剧烈的炎症反应及高致死率。对其分子机理进行研究发现,Lgr4基因敲除鼠中Wnt/β-catenin信号通路显著下调导致其肠上皮细胞在炎症损伤过程修复缺陷,最终引起肠上皮屏障被严重破坏。通过与APCmin小鼠杂交或者注射GSK3β抑制剂SB216763在Lgr4基因敲除鼠中激活Wnt信号通路,Paneth细胞的数目得到了部分的回复并且DSS诱导的炎症症状明显减轻,存活率也得到了显著的提高。综上所述,我们的研究表明,Lgr4在肠上皮自稳态维持过程中有着重要的作用,并且通过调节Wnt/β-catenin信号通路促进肠上皮在肠炎过程中的损伤修复。
The proliferation and differentiation of epithelial cells in the intestine are tightly regulated by Wnt signaling pathway. Lgr4is one of the newly identified R-Spondinl receptor potentiate Wnt signaling. However, how Lgr4regulates intestinal homeostasis remains elusive. By using an Lgr4gene-trap mouse strain which contains a β-gal reporter driven by endougenous Lgr4promoter we found Lgr4expresses mainly in cypts and predominantly in Paneth cells which constitute the potential niche for Lgr5positive intestinal stem cells (ISCs). Lgr4deficiency resulted in greatly reduced cell number of either Paneth cells or stem cells in the intestine. To explore the physiological role of Lgr4in intestinal inflammation, dextran sulfate sodium (DSS)-induced IBD model was employed. Intestinal inflammation was induced with DSS, followed by a recovery period. Intestinal inflammation symptoms and molecular mechanisms were examined. We found that Lgr4-/-mice exhibited dramatically higher susceptibility and mortality to DSS-induced inflammatory bowel disease (IBD) than WT mice. Mechanisim research determined downregulated Wnt/β-catenin signaling in the intestinal epithelium of Lgr4-/-mice. When Wnt/β-catenin signaling was re-activated by crossing with APCmin/+mice or by treating with a GSK-3β inhibitor, the number of Paneth cells was partially restored and the mortality caused by DSS-induced IBD was strikingly reduced in Lgr4deficient animals. Thus, Lgr4is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through modulation of the Wnt/β-catenin signaling pathway.
The proliferation and differentiation of epithelial cells in the intestine are tightly regulated by Wnt signaling pathway. Lgr4is one of the newly identified R-Spondinl receptor potentiate Wnt signaling. However, how Lgr4regulates intestinal homeostasis remains elusive. By using an Lgr4gene-trap mouse strain which contains a β-gal reporter driven by endougenous Lgr4promoter we found Lgr4expresses mainly in cypts and predominantly in Paneth cells which constitute the potential niche for Lgr5positive intestinal stem cells (ISCs). Lgr4deficiency resulted in greatly reduced cell number of either Paneth cells or stem cells in the intestine. To explore the physiological role of Lgr4in intestinal inflammation, dextran sulfate sodium (DSS)-induced IBD model was employed. Intestinal inflammation was induced with DSS, followed by a recovery period. Intestinal inflammation symptoms and molecular mechanisms were examined. We found that Lgr4-/-mice exhibited dramatically higher susceptibility and mortality to DSS-induced inflammatory bowel disease (IBD) than WT mice. Mechanisim research determined downregulated Wnt/β-catenin signaling in the intestinal epithelium of Lgr4-/-mice. When Wnt/β-catenin signaling was re-activated by crossing with APCmin/+mice or by treating with a GSK-3β inhibitor, the number of Paneth cells was partially restored and the mortality caused by DSS-induced IBD was strikingly reduced in Lgr4deficient animals. Thus, Lgr4is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through modulation of the Wnt/β-catenin signaling pathway.
引文
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