A noncanonical function of histidyl-tRNA synthetase: inhibition of vascular hyperbranching during zebrafish...

Histidyl-tRNA synthetase (Hars) catalyzes the ligation of histidine residues to cognate tRNA. Here, we demonstrate a noncanonical function of Hars in vascular development in zebrafish. We obtained a novel zebrafish cq34 mutant which exhibited hyperbranching of cranial and intersegmental blood vessels 48 h after fertilization. The gene responsible for this phenotype was identified as hars. We found the increased expression of cdh5 and vegfa in the hars mutant. Knockdown of cdh5 in the mutant reduced disordered connections of the hindbrain capillaries. Inhibition of vascular endothelial growth factor signaling suppressed the abnormal vascular branching observed in the mutant. Moreover, the human HARS mRNA rescued the vascular defects in the cq34 mutant. Thus, the noncanonical function of Hars regulates vascular development, mainly by modulating expression of cdh5 and vegfa.