A betaPix Pak2a signaling pathway regulates cerebral vascular stability in zebrafish.
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.
Liu
Jing
J
Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.
Fraser
Sherri D
SD
Faloon
Patrick W
PW
Rollins
Evvi Lynn
EL
Vom Berg
Johannes
J
Starovic-Subota
Olivera
O
Laliberte
Angie L
AL
Chen
Jau-Nian
JN
Serluca
Fabrizio C
FC
Childs
Sarah J
SJ
D017398:Alternative Splicing; D000818:Animals; D001808:Blood Vessels / Q000502:physiology; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002543:Cerebral Hemorrhage / Q000235:genetics; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004730:Endothelium, Vascular / Q000502:physiology; D005038:Ethylnitrosourea; D005091:Exons; D014644:Genetic Variation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D064067:Rho Guanine Nucleotide Exchange Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*; D054462:p21-Activated Kinases
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D029961:Zebrafish Proteins; C523516:Pak2a protein, zebrafish; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D005038:Ethylnitrosourea