
pak2a mutations cause cerebral hemorrhage in redhead zebrafish
Author(s) -
David A. Buchner,
Fengyun Su,
Jennifer S. Yamaoka,
Makoto Kamei,
Jordan A. Shavit,
Linda K. Barthel,
Beth McGee,
Julio D. Amigo,
Seong-Cheol Kim,
Andrew Hanosh,
Pudur Jagadeeswaran,
Daniel Goldman,
Nathan D. Lawson,
Pamela A. Raymond,
Brant M. Weinstein,
David Ginsburg,
Susan E. Lyons
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0700947104
Subject(s) - zebrafish , biology , microbiology and biotechnology , phenotype , angiogenesis , cdc42 , transgene , mutation , endothelial stem cell , kinase , cancer research , genetics , gene , in vitro
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 therhd phenotype is caused by a hypomorphic mutation inp21-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 anotherPAK2 ortholog,pak2b , in Pak2a-deficient embryos results in a more severe hemorrhagic phenotype, consistent with partially overlapping functions for these two orthologs. These data providein vivo evidence for a critical function of Pak2 in vascular integrity and demonstrate a severe disease phenotype resulting from loss of Pak2 function.