PDF(Pubmed)
Abstract：
Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway. We have previously reported that cerebral overexpression of furin promotes cognitive functions in mice. Here, by generating the brain-specific furin conditional knockout (cKO) mice, we investigated the role of furin in brain development. We found that furin deficiency caused early death and growth retardation. Magnetic resonance imaging showed severe hydrocephalus. In the brain of furin cKO mice, impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expression of RAB28, a ciliary vesicle protein. In line with the widespread neuronal loss, ependymal cell layers were damaged. Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice; and astrocyte overgrowth was accompanied by the reduced expression of SOX9, indicating a disrupted differentiation into ependymal cells. Together, whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis, dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin cKO mice. The structural and molecular alterations provided a clue for further studying the potential mechanisms of furin.
摘要：
弗林蛋白酶是在分泌途径中的反式高尔基体网络和细胞表面之间移动的前蛋白转化酶。我们先前已经报道了弗林蛋白酶的大脑过度表达促进小鼠的认知功能。这里,通过产生脑特异性弗林蛋白酶条件敲除（cKO）小鼠，我们研究了弗林在大脑发育中的作用。我们发现弗林蛋白酶缺乏导致早期死亡和生长迟缓。磁共振成像显示严重脑积水。在弗林cKO小鼠的大脑中，纤毛发生受损和微管结构的紊乱伴随着睫状囊泡蛋白RAB28的表达下调。与广泛的神经元丢失相一致，室管膜细胞层受损。进一步的蛋白质组学分析显示，在furincKO小鼠中，包括星形胶质细胞富集的ITGB8和BCAR1在内的细胞粘附分子发生了变化；星形胶质细胞过度生长伴随着SOX9表达的降低，表明分化为室管膜细胞的破坏。一起,而RAB28表达的改变与囊泡运输在纤毛发生中的作用相关，功能失调的星形胶质细胞可能参与导致furincKO小鼠脑积水的室管膜损伤。结构和分子的改变为进一步研究弗林蛋白酶的潜在机制提供了线索。
