title: Small GTPase Rap1 Is Essential for Mouse Development and Formation of Functional Vasculature.
abstract: BACKGROUND
  Small GTPase Rap1 has been implicated in a number of basic cellular functions, including cell-cell and cell-matrix adhesion, proliferation and regulation of polarity. Evolutionarily conserved, Rap1 has been studied in model organisms: yeast, Drosophila and mice. Mouse in vivo studies implicate Rap1 in the control of multiple stem cell, leukocyte and vascular cell functions. In vitro, several Rap1 effectors and regulatory mechanisms have been proposed. In particular, Rap1 has been implicated in maintaining epithelial and endothelial cell junction integrity and linked with cerebral cavernous malformations.
  
  
  BACKGROUND
  How Rap1 signaling network controls mammalian development is not clear. As a first step in addressing this question, we present phenotypes of murine total and vascular-specific Rap1a, Rap1b and double Rap1a and Rap1b (Rap1) knockout (KO) mice.
  
  
  CONCLUSIONS
  The majority of total Rap1 KO mice die before E10.5, consistent with the critical role of Rap1 in epithelial morphogenesis. At that time point, about 50% of Tie2-double Rap1 KOs appear grossly normal and develop normal vasculature, while the remaining 50% suffer tissue degeneration and show vascular abnormalities, including hemorrhages and engorgement of perineural vessels, albeit with normal branchial arches. However, no Tie2-double Rap1 KO embryos are present at E15.5, with hemorrhages a likely cause of death. Therefore, at least one Rap1 allele is required for development prior to the formation of the vascular system; and in endothelium-for the life-supporting function of the vasculature.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, 53201, United States of America.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chrzanowska-Wodnicka
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, 53201, United States of America.
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: White
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Quilliam
authors.affiliation: Division of Cardiovascular Medicine, Pediatric Cardiology, Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Whitehead
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D055786:Gene Knockout Techniques; D006470:Hemorrhage / Q000201:enzymology; D000075927:KRIT1 Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D020668:rap GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins