title: Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.
abstract: 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.
authors.affiliation: MGH Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
authors.forename: Kang Quan
authors.initials: KQ
authors.lastname: Hu
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Matheson
authors.forename: Madeleine R
authors.initials: MR
authors.lastname: Brouns
authors.forename: Barry
authors.initials: B
authors.lastname: Fine
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takami
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
mesh_terms: 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*
chemical_list: 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