Dlc1controls cardio-vascular development downstream of Vegfa/Kdrl/Nrp1 signaling in the zebrafish embryo

ABSTRACT The family of deleted-in-liver-cancer (dlc) genes encodes RhoGTPases and plays pivotal roles in cardiovascular development, but animal models for studying their functions are sparse due to early embryonic lethality. Gain and loss of function of dlc1 and dlc3 severely altered the growth of intersegmental vessels in the trunk of zebrafish embryos. Additionally, overexpression of dlc1 affected the growth of the common cardinal veins, but could rescue the arrest of angiogenesis induced by Vegfr2 inhibition, placing dlc1 downstream of kdrl signaling. Loss of dlc1 negatively affected the lumenization of the first aortic arch arteries and the lateral dorsal aortae. dlc1 mutants displayed a full obstruction in the early outflow tract during cardiac morphogenesis, which models to alterations in DLC1 detected in congenital heart defects in human patients. This study provides a functional in vivo characterization of dlc1 and dlc3 during vertebrate embryogenesis and places dlc1 as a key gene to control vascular development.