Abstract
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 cq34 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.
Highlights
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China
We obtained a novel zebrafish cq34 mutant with increased branching angiogenesis. We identified that these phenotypes are caused by a mutation in the post-transcriptional splice recognition site at the histidyl-tRNA synthetase genomic locus, which resulted in the deletion of exon 7
Our results suggest that the noncanonical function of histidyl-tRNA synthetase (Hars) in the regulation of vascular development mainly depends on the modulating the expression of cdh5 and vegfa
Summary
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China. The noncanonical function of Hars regulates vascular development, mainly by modulating expression of cdh and vegfa. Angiogenesis refers to the formation of new blood vessels by sprouting of endothelial cells (ECs) from preexisting vessels and subsequent proliferation, migration, and remodeling All of these processes are tightly regulated by a network of pro- and anti-angiogenic factors. Formed blood vessels connect to the existing vasculature to establish a functional circulatory loop that permits the transportation of fluids, nutrients, circulating cells, hormones, and gasses. To attain such morphology, the correct polarity and spatial redistribution of EC–EC junctions must be achieved.
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