A βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish

Liu, J., Fraser, S.D., Faloon, P.W., Rollins, E.L., Vom Berg, J., Starovic-Subota, O., Laliberte, A.L., Chen, J.N., Serluca, F.C., and Childs, S.J.
Proceedings of the National Academy of Sciences of the United States of America   104(35): 13990-13995 (Journal)
Registered Authors
Chen, Jau-Nian, Childs, Sarah J., Faloon, Patrick, Fraser, Sherri, Liu, Jing, Rollins, Evvi-Lynn, Serluca, Fabrizio
angiogenesis, hemorrhage, hydrocephalus
MeSH Terms
  • Alternative Splicing
  • Animals
  • Blood Vessels/physiology
  • Brain/pathology
  • Cell Cycle Proteins/genetics*
  • Cerebral Hemorrhage/genetics
  • Cerebrovascular Circulation/physiology*
  • Chromosome Mapping
  • Cloning, Molecular
  • Endothelium, Vascular/physiology
  • Ethylnitrosourea
  • Exons
  • Genetic Variation
  • Guanine Nucleotide Exchange Factors/deficiency
  • Guanine Nucleotide Exchange Factors/genetics*
  • Molecular Sequence Data
  • Protein Serine-Threonine Kinases/physiology*
  • Rho Guanine Nucleotide Exchange Factors
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
  • p21-Activated Kinases
17573532 Full text @ Proc. Natl. Acad. Sci. USA
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 zebrafish bubblehead (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 betaPix, a binding partner for the p21-activated kinase (Pak) and a guanine nucleotide exchange factor for Rac and Cdc42. betaPix is broadly expressed during embryonic development and is enriched in the brain and in large blood vessels. By knockdown of specific betaPix splice variants, we show that they play unique roles in embryonic vascular stabilization or hydrocephalus. Finally, we show that Pak2a signaling is downstream of betaPix. These data identify an essential in vivo role for betaPix and Pak2a during embryonic development and illuminate a previously unrecognized pathway specifically involved in cerebrovascular stabilization.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes