Institute of Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, University of Munich, Munich, Germany.
PLoS One. 2010 Dec 14;5(12):e14325. doi: 10.1371/journal.pone.0014325.
E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease.
To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen.
These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells.
E-钙黏蛋白是黏着连接的主要成分。小肠和结肠中 E-钙黏蛋白表达受损与肠道内稳态和屏障功能紊乱有关。E-钙黏蛋白的下调与肠致病性细菌感染和克罗恩病的发病机制有关。
为了从遗传学上阐明 E-钙黏蛋白在肠道内稳态和上皮防御线维持中的功能，我们在小鼠肠道上皮细胞中条件性地使 Cdh1 基因失活。小肠和结肠中 Cdh1 基因的失活导致血性腹泻，伴有细胞凋亡和细胞脱落增强，导致 6 天内危及生命的疾病。E-钙黏蛋白的缺失导致细胞沿隐窝-绒毛轴更快地迁移，并扰乱细胞分化。杯状细胞和潘氏细胞（肠道先天免疫系统的主要细胞谱系）的成熟和定位严重受损。抗细菌防御素的表达减少，并且小鼠在清除肠腔中的肠致病性细菌方面存在缺陷。
这些结果突出了 E-钙黏蛋白在维持肠道上皮防御的两个组成部分中的核心功能：E-钙黏蛋白通过提供机械完整性为肠道上皮衬里的正常功能提供了必要条件，并且是潘氏细胞和杯状细胞正常成熟的前提条件。
