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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Mcgee, Beth Lyons, Susan E. Kim, Seongcheol Ginsburg, David Kamei, Makoto Lawson, Nathan D. Hanosh, Andrew W. Weinstein, Brant M. Shavit, Jordan A. Jagadeeswaran, Pudur Su, Fengyun Amigo, Julio D. Goldman, Daniel Yamaoka, Jennifer S. Raymond, Pamela A. Barthel, Linda K. Buchner, David A. |
| Description | Author Affiliation: Buchner DA ( Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 35 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cerebral Hemorrhage Genetics Mutation Protein-Serine-Threonine Kinases Zebrafish Alternative Splicing Animals Embryology Cerebrovascular Circulation Chromosome Mapping Embryo, Nonmammalian Genes, Recessive Genetic Variation Polymorphism, Restriction Fragment Length Deficiency RNA Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic Zebrafish Proteins P21-Activated Kinases Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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