The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development.
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.
Brouns
M R
MR
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Matheson
S F
SF
Hu
K Q
KQ
Delalle
I
I
Caviness
V S
VS
Silver
J
J
Bronson
R T
RT
Settleman
J
J
D000483:Alleles; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005124:Eye Abnormalities / Q000196:embryology / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D020690:GTPase-Activating Proteins; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016548:Prosencephalon / Q000002:abnormalities; D011493:Protein Kinase C / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction
C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D011493:Protein Kinase C