Open AccessA βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish
Author(s) -
Jing Liu,
Sherri D. Fraser,
Patrick W. Faloon,
Evvi Lynn Rollins,
Johannes vom Berg,
Olivera Starovic-Subota,
Angie L. Laliberte,
Jau-Nian Chen,
Fabrizio C. Serluca,
Sarah Childs
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0700825104
Subject(s) - zebrafish , biology , guanine nucleotide exchange factor , microbiology and biotechnology , gene knockdown , mutation , embryonic stem cell , mutant , signal transduction , cdc42 , blood–brain barrier , genetics , neuroscience , central nervous system , gene
The vasculature tailors to the needs of different tissues and organs. Molecular, structural, and functional specializations are observed in different vascular beds, but few genetic models give insight into how these differences arise. We identify a unique cerebrovascular mutation in the zebrafish affecting the integrity of blood vessels supplying the brain. The zebrafishbubblehead (bbh ) mutant exhibits hydrocephalus and severe cranial hemorrhage during early embryogenesis, whereas blood vessels in other regions of the embryo appear intact. Here we show that hemorrhages are associated with poor cerebral endothelial–mesenchymal contacts and an immature vascular pattern in the head. Positional cloning of bbh reveals a hypomorphic mutation in βPix, a binding partner for the p21-activated kinase (Pak) and a guanine nucleotide exchange factor for Rac and Cdc42. βPix is broadly expressed during embryonic development and is enriched in the brain and in large blood vessels. By knockdown of specific βPix splice variants, we show that they play unique roles in embryonic vascular stabilization or hydrocephalus. Finally, we show that Pak2a signaling is downstream of βPix. These data identify an essentialin vivo role for βPix and Pak2a during embryonic development and illuminate a previously unrecognized pathway specifically involved in cerebrovascular stabilization.