title: pak2a mutations cause cerebral hemorrhage in redhead zebrafish.
abstract: The zebrafish is a powerful model for studying vascular development, demonstrating remarkable conservation of this process with mammals. Here, we identify a zebrafish mutant, redhead (rhd(mi149)), that exhibits embryonic CNS hemorrhage with intact gross development of the vasculature and normal hemostatic function. We show that the rhd phenotype is caused by a hypomorphic mutation in p21-activated kinase 2a (pak2a). PAK2 is a kinase that acts downstream of the Rho-family GTPases CDC42 and RAC and has been implicated in angiogenesis, regulation of cytoskeletal structure, and endothelial cell migration and contractility among other functions. Correction of the Pak2a-deficient phenotype by Pak2a overexpression depends on kinase activity, implicating Pak2 signaling in the maintenance of vascular integrity. Rescue by an endothelial-specific transgene further suggests that the hemorrhage seen in Pak2a deficiency is the result of an autonomous endothelial cell defect. Reduced expression of another PAK2 ortholog, pak2b, in Pak2a-deficient embryos results in a more severe hemorrhagic phenotype, consistent with partially overlapping functions for these two orthologs. These data provide in vivo evidence for a critical function of Pak2 in vascular integrity and demonstrate a severe disease phenotype resulting from loss of Pak2 function.
authors: Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: David A
authors: DA
authors: Buchner
authors: Fengyun
authors: F
authors: Su
authors: Jennifer S
authors: JS
authors: Yamaoka
authors: Makoto
authors: M
authors: Kamei
authors: Jordan A
authors: JA
authors: Shavit
authors: Linda K
authors: LK
authors: Barthel
authors: Beth
authors: B
authors: McGee
authors: Julio D
authors: JD
authors: Amigo
authors: Seongcheol
authors: S
authors: Kim
authors: Andrew W
authors: AW
authors: Hanosh
authors: Pudur
authors: P
authors: Jagadeeswaran
authors: Daniel
authors: D
authors: Goldman
authors: Nathan D
authors: ND
authors: Lawson
authors: Pamela A
authors: PA
authors: Raymond
authors: Brant M
authors: BM
authors: Weinstein
authors: David
authors: D
authors: Ginsburg
authors: Susan E
authors: SE
authors: Lyons
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002543:Cerebral Hemorrhage / Q000196:embryology / Q000235:genetics*; D002560:Cerebrovascular Circulation / Q000235:genetics; D002874:Chromosome Mapping; D004625:Embryo, Nonmammalian; D005808:Genes, Recessive; D014644:Genetic Variation; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics; D054462:p21-Activated Kinases
chemical_list: D029961:Zebrafish Proteins; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases
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