Loss of Smad5 leads to the disassembly of the apical junctional complex and increased susceptibility to experimental colitis
Loss of Smad5 leads to the disassembly of the apical junctional complex and increased susceptibility to experimental colitis
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DOI：
10.1152/ajpgi.00041.2010
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发表时间：
2011-04-01
影响因子：
4.5
通讯作者：
Perreault, Nathalie
中科院分区：
文献类型：
--
作者：
Allaire, Joannie M.;Darsigny, Mathieu;Perreault, Nathalie
Allaire JM，Darsigny M，MarCoux SS，Roy SAB，Schmore JF，umans L，Zwijsen A，Boudreau F，Perreault N。丢失Smad5会导致顶端连接复合体的解体，并增加对实验性结肠炎的易感性。Am J Physiol Gasterintest肝脏生理学300：G586-G597,2011。2011年1月6日首次出版；DOI：10.1152/ajpgi.00041.2010。-炎症性肠病经常损害肠上皮细胞黏附和迁移特性的调节。尽管骨形态发生蛋白(BMP)信号在肠道病理中的作用越来越引起人们的兴趣，但对单个Smads在肠道上皮功能中所起的具体作用却知之甚少。在目前的研究中，我们建立了一种BMP信号通路的Smad5转录效应因子仅在肠道上皮细胞中缺失的小鼠模型。免疫荧光和Western印迹分析细胞增殖、迁移和心尖连接复合体(AJC)蛋白的表达。采用定量聚合酶链式反应(QPCR)技术检测正常对照和IBD患者肠组织中Smad5基因的转录表达。用葡聚糖硫酸钠(DSS)诱导Smad5(Delta IEC)和对照组小鼠实验性结肠炎，观察其临床和组织学症状。Smad5的缺失导致肠上皮细胞过度迁移和claudin-1、claudin-2表达的失控。E-钙粘附素在Smad5(Delta IEC)小鼠中同样表达，但从AJC移位到细胞质。对人类IBD患者样本中Smad5基因表达的分析显示，在克罗恩病和溃疡性结肠炎样本中，Smad5基因转录显著下调。暴露于实验性DSS结肠炎的Smad5(Delta IEC)小鼠明显更容易患上这种疾病，并在恢复期损害伤口愈合。我们的结果支持Smad5部分参与了肠道上皮细胞BMP信号的传递。此外，上皮性Smad5的缺失导致AJC分解，从而导致细胞迁移的松弛，增加了对实验性结肠炎的易感性，并损害了伤口的愈合。
Allaire JM, Darsigny M, Marcoux SS, Roy SAB, Schmouth JF, Umans L, Zwijsen A, Boudreau F, Perreault N. Loss of Smad5 leads to the disassembly of the apical junctional complex and increased susceptibility to experimental colitis. Am J Physiol Gastrointest Liver Physiol 300: G586-G597, 2011. First published January 6, 2011; doi: 10.1152/ajpgi.00041.2010.-The regulation of intestinal epithelial cell adhesion and migratory properties is often compromised in inflammatory bowel disease (IBD). Despite an increasing interest in bone morphogenetic protein (Bmp) signaling in gut pathologies, little is known of the specific roles played by individual Smads in intestinal epithelial functions. In the present study, we generated a mouse model with deletion of Smad5 transcriptional effector of the Bmp signaling pathway exclusively in the intestinal epithelium. Proliferation, migration, and apical junctional complex (AJC) protein expression were analyzed by immunofluorescence and Western blot. Human intestinal biopsies from control and IBD patients were analyzed for SMAD5 gene transcript expression by quantitative PCR (qPCR). Smad5(Delta IEC) and control mice were subjected to dextran sulfate sodium (DSS)-induced experimental colitis, and their clinical and histological symptoms were assessed. Loss of Smad5 led to intestinal epithelial hypermigration and deregulation of the expression of claudin-1 and claudin-2. E-cadherin was found to be equally expressed but displaced from the AJC to the cytoplasm in Smad5(Delta IEC) mice. Analysis of SMAD5 gene expression in human IBD patient samples revealed a significant downregulation of the gene transcript in Crohn's disease and ulcerative colitis samples. Smad5(Delta IEC) mice exposed to experimental DSS colitis were significantly more susceptible to the disease and had impaired wound healing during the recovery phase. Our results support that Smad5 is partly responsible for mediating Bmp signals in intestinal epithelial cells. In addition, deficiency in epithelial Smad5 leads to the deregulation of cell migration by disassembling the AJC with increasing susceptibility to experimental colitis and impairment in wound healing.