Cdc42GAP regulates c-Jun N-terminal kinase (JNK)-mediated apoptosis and cell number during mammalian perinatal growth.
Rho family GTPase Cdc42 is known to regulate polarity and growth in lower eukaryotes, but its physiologic function in mammals has yet to be determined. Here we have disrupted cdc42gap, a ubiquitously expressed negative regulator of Cdc42, in mice. Cdc42GAP(-/-) embryonic fibroblasts and various organs displayed significantly elevated Cdc42 activity. The embryonic and neonatal homozygous mice were reduced in size by approximately 25-40% and suffered severe growth retardation. Major organs from Cdc42GAP(-/-) mice were proportionally smaller because of decreased cell number. Basal apoptosis was increased in Cdc42GAP(-/-) cells and tissues, and this was attributed to altered c-Jun N-terminal kinase apoptotic signals. These results reveal a role of Cdc42GAP in mammalian perinatal growth and implicate the c-Jun N-terminal kinase-mediated apoptosis machinery as a Cdc42 effector pathway in vivo.
Wang
Lei
L
Division of Experimental Hematology, Children's Hospital Medical Center, Molecular Developmental Biology Graduate Program, University of Cincinnati, Cincinnati, OH 45229, USA.
Yang
Linda
L
Burns
Kevin
K
Kuan
Chia-Yi
CY
Zheng
Yi
Y
D000818:Animals; D017209:Apoptosis; D049628:Body Size / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C505158:Arhgap1 protein, mouse; D020690:GTPase-Activating Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020764:cdc42 GTP-Binding Protein