Hypoxia-inducible factor 2-alpha participates in the regulation of intersegmental vessels angiogenesis and neuromast deposition

Abstract

Subtle morphogenesis begins during trunk development after the segmentation period in zebrafish. Sprouting angiogenesis forms the trunk vascular system after the extension of the dorsal aorta and cardinal veins. The posterior lateral line primordium migrates from head to tail, forming the sensory organs on the skin. It is still unclear whether this morphogenesis requires several master regulators to control the ongoing process. Hypoxia-inducible factor 2-alpha (Hif2-alpha) plays an essential role in the maturation of both central neural system and digestive system during embryogenesis. We hypothesized that Hif2-alpha also regulates trunk development. Through loss-of-function experiments, we found that Hif2-alpha, but not Hif1-alpha, is necessary for angiogenesis and the formation of neuromasts in the trunk. Hif2-alpha regulates the expression of spleen tyrosine kinase (Syk), maintaining sprouting in the trunk. Furthermore, Hif2-alpha also regulates lymphoid enhancer factor 1 (Lef1), moderating the deposition of neuromasts. The regulation of Syk and Lef1 expression by Hif2-alpha occurs through the direct binding of Hif2-alpha to the hypoxia-responsive elements (HRE) of syk and lef1. This study provides the first evidence that Hif2-alpha plays a pivotal role in the vertebrate embryonic development of intersegmental vessels and the mechanosensory system in the zebrafish trunk.