Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.
Rho GTPases regulate several aspects of tissue morphogenesis during animal development. We found that mice lacking the Rho-inhibitory protein, p190-B RhoGAP, are 30% reduced in size and exhibit developmental defects strikingly similar to those seen in mice lacking the CREB transcription factor. In p190-B RhoGAP-deficient mice, CREB phosphorylation is substantially reduced in embryonic tissues. Embryo-derived cells contain abnormally high levels of active Rho protein, are reduced in size, and exhibit defects in CREB activation upon exposure to insulin or IGF-1. The cell size defect is rescued by expression of constitutively activated CREB, and in wild-type cells, expression of activated Rho or dominant-negative CREB results in reduced cell size. Together, these results suggest that activity of the Rho GTPase modulates a signal from insulin/IGFs to CREB that determines cell size and animal size during embryogenesis.
Sordella
Raffaella
R
MGH Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Classon
Marie
M
Hu
Kang Quan
KQ
Matheson
Stephen F
SF
Brouns
Madeleine R
MR
Fine
Barry
B
Zhang
Le
L
Takami
Hiroya
H
Yamada
Yoshihiko
Y
Settleman
Jeffrey
J
D000818:Animals; D001824:Body Constitution; D048429:Cell Size; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005314:Embryonic and Fetal Development; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins