RT Journal Article
SR Electronic
T1 <em>pak2a</em> mutations cause cerebral hemorrhage in <em>redhead</em> zebrafish
JF Proceedings of the National Academy of Sciences
JO Proc Natl Acad Sci USA
FD National Academy of Sciences
SP 13996
OP 14001
DO 10.1073/pnas.0700947104
VO 104
IS 35
A1 Buchner, David A.
A1 Su, Fengyun
A1 Yamaoka, Jennifer S.
A1 Kamei, Makoto
A1 Shavit, Jordan A.
A1 Barthel, Linda K.
A1 McGee, Beth
A1 Amigo, Julio D.
A1 Kim, Seongcheol
A1 Hanosh, Andrew W.
A1 Jagadeeswaran, Pudur
A1 Goldman, Daniel
A1 Lawson, Nathan D.
A1 Raymond, Pamela A.
A1 Weinstein, Brant M.
A1 Ginsburg, David
A1 Lyons, Susan E.
YR 2007
UL http://www.pnas.org/content/104/35/13996.abstract
AB 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 (rhdmi149 ), 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.