Collagen VI suppresses fibronectin-induced enteric neural crest cell migration by downregulation of focal adhesion proteins
Collagen VI suppresses fibronectin-induced enteric neural crest cell migration by downregulation of focal adhesion proteins
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DOI：
10.1016/j.bbrc.2017.11.184
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发表时间：
2018-01-01
影响因子：
3.1
通讯作者：
Kohno, Miyuki
中科院分区：
文献类型：
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作者：
Nishida, Shoichi;Yoshizaki, Hisayoshi;Kohno, Miyuki
肠神经系统（ENS）是一个神经元和胶质细胞网络，源自肠神经嵴细胞（ENCC），对于调节结肠蠕动活动至关重要。ENCC沿胃肠道沿着迁移以形成ENS，并且ENCC能动性的破坏导致ENS病症，例如先天性巨结肠。先前的ENCC移植实验表明，ENCC可以在E13.5时侵入离体小鼠肠道，但在E15.5后不能。我们假设肠道中年龄特异性微环境的改变是ENCC侵袭/迁移的原因。在这里，我们比较了在E11.5和E15.5之间的肠道中的基因表达，并确定了1355个差异表达的转录本。其中，我们发现编码细胞外基质（ECM）蛋白的基因富集。值得注意的是，胶原VI（ColVI）家族成员在E15.5小鼠肠中的mRNA和蛋白质水平上调，而纤连蛋白（FN）下调;然而，这两种蛋白质在E15.5共定位。为了了解ColVI和FN在ENCC迁移中的机制，我们检查了神经球或个体ENCC对ECM的粘附能力。ColVI抑制FN诱导的ENCC扩展/迁移，而ColVI诱导的形态学狭窄的ENCC扩展和弱应力纤维形成与FN相比。此外，在含有ColVI的平板上培养的ENCC中，粘着斑复合物的成员p130（cas）的表达和磷酸化减少。这些数据表明ColVI在ENCC迁移中的抑制作用，并表明肠中的ColVI抑制可能代表无神经节结肠疾病的新治疗策略。(C)2017爱思唯尔公司All rights reserved.
The enteric nervous system (ENS) is a network of neurons and glia that are derived from enteric neural crest cells (ENCCs) and essential for regulating peristaltic activity of the colon. ENCCs migrate along the gastrointestinal tract to form the ENS, and disruption of ENCC motility leads to ENS disorders, such as Hirschsprung's disease. Previous ENCC-transplant experiments show that ENCCs can invade into isolated mouse intestines by age E13.5, but not after E15.5. We hypothesized that altered age-specific micro environments in the intestine are responsible for ENCC invasion/migration. Here, we compared gene expression in the intestine between at E11.5 and E15.5 and identified 1355 differentially expressed transcripts. Among these, we found that genes encoding extracellular matrix (ECM) proteins were enriched. Notably, collagen VI (ColVI) family members were upregulated in the E15.5 mouse intestine at the mRNA and protein levels, whereas fibronectin (FN) was downregulated; however, both proteins showed colocalization at E15.5. To understand the mechanisms of ColVI and FN in ENCC migration, we examined neurosphere or individual ENCC-adherence capabilities toward the ECM. ColVI suppressed FN induced ENCC spreading/migration, whereas ColVI induced morphologically narrow ENCC spreading and weak stress-fiber formation as compared with those with FN. Additionally, in ENCCs cultured on plates containing ColVI, the expression and phosphorylation of p130(cas), a members of focal adhesion complexes, was reduced. These data indicated an inhibitory role of ColVI in ENCC migration and suggested that ColVI suppression in the intestine might represent a novel therapeutic strategy for aganglionic colonic diseases. (C) 2017 Elsevier Inc. All rights reserved.