Distinct but overlapping functions for the closely related p190 RhoGAPs in neural development.
The p190 RhoGAPs, p190A and p190B, are highly related GTPase-activating proteins for the Rho GTPases. Rho GTPases and p190A reportedly control various aspects of brain development, and we hypothesized that p190B would be likewise involved in neuronal development. We find that like p190A, p190B is prominently expressed in the developing and adult brain. Unlike p190A, p190B is not abundantly tyrosine phosphorylated. We further demonstrate, using p190B-deficient mice, that p190B is required for normal brain development. Mice lacking p190B display several major defects, including (1) deficits in the formation of major forebrain commissures, including the corpus callosum and anterior commissure, (2) dilation of the lateral ventricles, suggesting inhibition of neurogenesis and/or survival, (3) thinning of the neocortical intermediate zone, suggesting defects in neuronal differentiation and/or axonal outgrowth, and (4) impaired neuronal differentiation. These defects are similar to, but distinct from, those described in p190A-deficient mice. RNA interference-mediated knockdown of neither p190 protein results in significant inhibition of neurite outgrowth in neuroblastoma cells, despite an apparent increase in RhoA activity. We conclude that p190 RhoGAPs control pivotal aspects of neural development, including neuronal differentiation and process outgrowth, and that these effects are mediated by signaling systems that include, but are not limited to, RhoA.
Matheson
Stephen F
SF
Department of Biology, Calvin College, Grand Rapids, MI, USA.
Hu
Kang-Quan
KQ
Brouns
Madeleine R
MR
Sordella
Raffaella
R
VanderHeide
John D
JD
Settleman
Jeffrey
J
D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000002:abnormalities / Q000166:cytology / Q000378:metabolism
C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D012097:Repressor Proteins