Buchner, D.A., Su, F., Yamaoka, J.S., Kamei, M., Shavit, J.A., Barthel, L.K., McGee, B., Amigo, J.D., Kim, S., Hanosh, A.W., Jagadeeswaran, P., Goldman, D., Lawson, N.D., Raymond, P.A., Weinstein, B.M., Ginsburg, D., and Lyons, S.E. (2007) pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci U S A 104(35): 13996-140001.
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.