Rac1 is essential for basement membrane-dependent epiblast survival.
During murine peri-implantation development, the egg cylinder forms from a solid cell mass by the apoptotic removal of inner cells that do not contact the basement membrane (BM) and the selective survival of the epiblast epithelium, which does. The signaling pathways that mediate this fundamental biological process are largely unknown. Here we demonstrate that Rac1 ablation in embryonic stem cell-derived embryoid bodies (EBs) leads to massive apoptosis of epiblast cells in contact with the BM. Expression of wild-type Rac1 in the mutant EBs rescues the BM-contacting epiblast, while expression of a constitutively active Rac1 additionally blocks the apoptosis of inner cells and cavitation, indicating that the spatially regulated activation of Rac1 is required for epithelial cyst formation. We further show that Rac1 is activated through integrin-mediated recruitment of the Crk-DOCK180 complex and mediates BM-dependent epiblast survival through activating the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. Our results reveal a signaling cascade triggered by cell-BM interactions essential for epithelial morphogenesis.
He
Xiaowen
X
Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Liu
Jie
J
Qi
Yanmei
Y
Brakebusch
Cord
C
Chrostek-Grashoff
Anna
A
Edgar
David
D
Yurchenco
Peter D
PD
Corbett
Siobhan A
SA
Lowry
Stephen F
SF
Graham
Alan M
AM
Han
Yaling
Y
Li
Shaohua
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001485:Basement Membrane / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology; D005855:Germ Layers / Q000166:cytology* / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
C476798:Crk protein, mouse; C528110:Dock180 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D009479:Neuropeptides; D050737:Proto-Oncogene Proteins c-crk; C484602:Rac1 protein, mouse; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
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