Brouns M R, Matheson S F, Hu K Q, Delalle I, Caviness V S, Silver J, Bronson R T, Settleman J
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Development. 2000 Nov;127(22):4891-903. doi: 10.1242/dev.127.22.4891.
Rho GTPases direct actin rearrangements in response to a variety of extracellular signals. P190 RhoGAP (GTPase activating protein) is a potent Rho regulator that mediates integrin-dependent adhesion signaling in cultured cells. We have determined that p190 RhoGAP is specifically expressed at high levels throughout the developing nervous system. Mice lacking functional p190 RhoGAP exhibit several defects in neural development that are reminiscent of those described in mice lacking certain mediators of neural cell adhesion. The defects reflect aberrant tissue morphogenesis and include abnormalities in forebrain hemisphere fusion, ventricle shape, optic cup formation, neural tube closure, and layering of the cerebral cortex. In cells of the neural tube floor plate of p190 RhoGAP mutant mice, polymerized actin accumulates excessively, suggesting a role for p190 RhoGAP in the regulation of +Rho-mediated actin assembly within the neuroepithelium. Significantly, several of the observed tissue fusion defects seen in the mutant mice are also found in mice lacking MARCKS, the major substrate of protein kinase C (PKC), and we have found that p190 RhoGAP is also a PKC substrate in vivo. Upon either direct activation of PKC or in response to integrin engagement, p190 RhoGAP is rapidly translocated to regions of membrane ruffling, where it colocalizes with polymerized actin. Together, these results suggest that upon activation of neural adhesion molecules, the action of PKC and p190 RhoGAP leads to a modulation of Rho GTPase activity to direct several actin-dependent morphogenetic processes required for normal neural development.
Rho GTP酶响应多种细胞外信号指导肌动蛋白重排。P190 RhoGAP（GTP酶激活蛋白）是一种强效的Rho调节剂，介导培养细胞中整合素依赖性黏附信号传导。我们已经确定p190 RhoGAP在整个发育中的神经系统中特异性高表达。缺乏功能性p190 RhoGAP的小鼠在神经发育中表现出若干缺陷，这些缺陷让人联想到在缺乏某些神经细胞黏附介质的小鼠中所描述的缺陷。这些缺陷反映了异常的组织形态发生，包括前脑半球融合、脑室形状、视杯形成、神经管闭合以及大脑皮质分层异常。在p190 RhoGAP突变小鼠神经管底板的细胞中，聚合肌动蛋白过度积累，表明p190 RhoGAP在调节神经上皮内Rho介导的肌动蛋白组装中发挥作用。值得注意的是，在突变小鼠中观察到的几种组织融合缺陷在缺乏蛋白激酶C（PKC）的主要底物MARCKS的小鼠中也有发现，并且我们发现p190 RhoGAP在体内也是PKC的底物。在直接激活PKC或响应整合素结合后，p190 RhoGAP迅速转位至膜皱褶区域，在那里它与聚合肌动蛋白共定位。总之，这些结果表明，在神经黏附分子激活后，PKC和p190 RhoGAP的作用导致Rho GTP酶活性的调节，以指导正常神经发育所需的几种肌动蛋白依赖性形态发生过程。
