pak2a mutations cause cerebral hemorrhage in redhead zebrafish.
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.
Buchner
David A
DA
Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Su
Fengyun
F
Yamaoka
Jennifer S
JS
Kamei
Makoto
M
Shavit
Jordan A
JA
Barthel
Linda K
LK
McGee
Beth
B
Amigo
Julio D
JD
Kim
Seongcheol
S
Hanosh
Andrew W
AW
Jagadeeswaran
Pudur
P
Goldman
Daniel
D
Lawson
Nathan D
ND
Raymond
Pamela A
PA
Weinstein
Brant M
BM
Ginsburg
David
D
Lyons
Susan E
SE
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
D029961:Zebrafish Proteins; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases
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