PDF(Pubmed)
Abstract：
The primary cilium decorates most eukaryotic cells and regulates tissue morphogenesis and maintenance. Structural or functional defects of primary cilium result in ciliopathies, congenital human disorders affecting multiple organs. Pathogenic variants in the ciliogenesis and planar cell polarity effectors (CPLANE) genes FUZZY, INTU and WDPCP disturb ciliogenesis, causing severe ciliopathies in humans and mice. Here, we show that the loss of Fuzzy in mice results in defects of primary cilia, accompanied by increased RhoA activity and excessive actin polymerization at the basal body. We discovered that, mechanistically, Fuzzy interacts with and recruits the negative actin regulator ARHGAP35 (also known as p190A RhoGAP) to the basal body. We identified genetic interactions between the two genes and found that a mutant ArhGAP35 allele increases the severity of phenotypic defects observed in Fuzzy-/- mice. Based on our findings, we propose that Fuzzy regulates ciliogenesis by recruiting ARHGAP35 to the basal body, where the latter likely restricts actin polymerization and modifies the actin network. Our study identifies a mechanism whereby CPLANE proteins control both actin polymerization and primary cilium formation.
摘要：
初级纤毛装饰大多数真核细胞并调节组织形态发生和维持。原发性纤毛的结构或功能缺陷导致纤毛病，影响多个器官的先天性人类疾病。纤毛发生和平面细胞极性效应子（CPLANE）基因FUZZY，INTU和WDPCP干扰纤毛发生，在人类和小鼠中引起严重的纤毛病变。这里,我们表明，小鼠的Fuzzy丢失会导致初级纤毛缺陷，伴随着RhoA活性的增加和基体上肌动蛋白的过度聚合。我们发现,机械上,Fuzzy与负肌动蛋白调节剂ARHGAP35（也称为p190ARhoGAP）相互作用并将其募集到基体。我们确定了两个基因之间的遗传相互作用，并发现突变的ArhGAP35等位基因增加了Fuzzy-/-小鼠中观察到的表型缺陷的严重程度。根据我们的发现,我们建议Fuzzy通过将ARHGAP35招募到基体来调节纤毛生成，后者可能限制肌动蛋白聚合并修改肌动蛋白网络。我们的研究确定了CPLANE蛋白控制肌动蛋白聚合和初级纤毛形成的机制。
