Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum
Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum
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DOI：
10.1002/cm.21292
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发表时间：
2016-04-01
期刊：
影响因子：
2.9
通讯作者：
Mooseker, Mark S.
中科院分区：
文献类型：
--
作者：
Hegan, Peter S.;Chandhoke, Surjit K.;Mooseker, Mark S.
遗传学研究表明，编码肌球蛋白IXb(Myo9b)的MYO9B基因是炎症性肠病(IBD)的易感基因。Myo9b是一种带有Rho GTPase激活结构域(RhoGAP)的马达蛋白。此外，我们最近发现，在肠道上皮细胞系中敲除Myo9b会损害伤口愈合和屏障功能。在这里，我们调查了缺乏Myo9b的小鼠是否存在肠道屏障功能受损和IBD的特征。Myo9b基因敲除(KO)小鼠表现出体重增加和粪便潜血(胃肠道出血的指标)受损，整个肠轴可检测到肠上皮细胞凋亡增加。组织学分析显示肠粘膜损伤，最常见于回肠，包括浅表溃疡和中性粒细胞浸润。局灶性病变含有中性粒细胞，超微结构检查证实上皮不连续，细胞外基质沉积。我们还观察到KO小鼠的粘膜屏障功能受损。KO回肠的跨上皮电阻比WT回肠小3倍。肠粘膜对高分子右旋糖苷也具有渗透性，这可能是由于粘膜表面溃疡的存在。与紧密连接相关的ZO-1丢失，与侧膜相关的E-钙粘附素减少，与末端网络相关的细胞角蛋白细丝丢失。与KO中Rho活性增加一致的是，基于磷酸化Myo2调节轻链的定位，激活的肌球蛋白II(Myo2)在心尖下的表达增加。在野生型和Myo9b KO小鼠中，除了延迟发病时间外，在葡聚糖硫酸钠诱导的结肠炎和致死率方面没有观察到差异。(C)2016威利期刊公司。
Genetic studies have implicated MYO9B, which encodes myosin IXb (Myo9b), a motor protein with a Rho GTPase activating domain (RhoGAP), as a susceptibility gene for inflammatory bowel disease (IBD). Moreover, we have recently shown that knockdown of Myo9b in an intestinal epithelial cell line impairs wound healing and barrier function. Here, we investigated whether mice lacking Myo9b have impaired intestinal barrier function and features of IBD. Myo9b knock out (KO) mice exhibit impaired weight gain and fecal occult blood (indicator of gastrointestinal bleeding), and increased intestinal epithelial cell apoptosis could be detected along the entire intestinal axis. Histologic analysis revealed intestinal mucosal damage, most consistently observed in the ileum, which included superficial ulceration and neutrophil infiltration. Focal lesions contained neutrophils and ultrastructural examination confirmed epithelial discontinuity and the deposition of extracellular matrix. We also observed impaired mucosal barrier function in KO mice. Transepithelial electrical resistance of KO ileum is >3 fold less than WT ileum. The intestinal mucosa is also permeable to high molecular weight dextran, presumably due to the presence of mucosal surface ulcerations. There is loss of tight junction-associated ZO-1, decreased lateral membrane associated E-cadherin, and loss of terminal web associated cytokeratin filaments. Consistent with increased Rho activity in the KO, there is increased subapical expression of activated myosin II (Myo2) based on localization of phosphorylated Myo2 regulatory light chain. Except for a delay in disease onset in the KO, no difference in dextran sulfate sodium-induced colitis and lethality was observed between wild-type and Myo9b KO mice. (c) 2016 Wiley Periodicals, Inc.