Hif-1α paralogs play a role in the hypoxic ventilatory response of larval and adult zebrafish (Danio rerio)

Abstract

Hypoxia inducible factor (Hif) 1α, an extensively studied transcription factor, is involved in the regulation of many biological processes in hypoxia including the hypoxic ventilatory response. In zebrafish, there are two paralogs of Hif-1α (Hif-1A and Hif-1B), but little is known about the specific roles or potential sub-functionalization of the paralogs in response to hypoxia. Using knockout lines of Hif-1α paralogs, we examined their involvement in the hypoxic ventilatory response, measured as ventilation frequency (fV) in larval and adult zebrafish (Danio rerio). In wild-type zebrafish, fV increased across developmental time [4 days post fertilization (dpf), 7 dpf, 10 dpf and 15 dpf] in response to hypoxia (55 mmHg). In contrast, the Hif-1B knockout fish did not exhibit an increase in hypoxic fV at 4 dpf. Similar to wild-types, as larvae of all knockout lines developed, the magnitude of fV increased but to a lesser degree than in the wild-type larvae, until 15 dpf at which point there was no difference among the genotypes. In adult zebrafish, only in Hif-1B knockout fish was there an attenuation in fV during sustained exposure to 30 mmHg for 1 h but no effect when exposed for a shorter duration to progressive hypoxia. The mechanism of action of Hif-1α, in part, may be through its downstream target, nitric oxide synthase (NOS), and its product, nitric oxide (NO). Overall, the effect of each Hif-1α paralog on the hypoxic ventilatory response of zebrafish varies over development and is dependent on the type of hypoxic stress.