Hypoxia-inducible transcription factors in fish: expression, function and interconnection with the circadian clock.

The hypoxia-inducible transcription factors are key regulators for the physiological response to low oxygen availability. In vertebrates, typically three Hif-α isoforms, Hif-1α, Hif-2α and Hif-3α, are expressed, each of which, together with Hif-1β, may form a functional heterodimer under hypoxic conditions, controlling expression of hundreds of genes. A teleost-specific whole-genome duplication complicates the analysis of isoform-specific functions in fish, but recent studies suggest that the existence of paralogues of a specific isoform opens up the possibility for a subfunctionalization. In contrast to during development inside the uterus, fish eggs are freely accessible and studies analyzing Hif expression in fish embryos during development have revealed that Hif proteins are not only controlling the hypoxic response, but are also crucial for proper development and organ differentiation. Significant advances have been made in our knowledge about tissue-specific functions of Hif proteins, especially with respect to gill or gonadal tissue. The hypoxia signalling pathway is known to be tightly and mutually intertwined with the circadian clock in zebrafish and mammals. Recently, a mechanistic explanation for the hypoxia-induced dampening of the transcriptional clock was detected in zebrafish, including also metabolically induced alterations of cellular redox signalling. In turn, MAP kinase-mediated H2O2 signalling modulates the temporal expression of Hif-1α protein, similar to the redox regulation of the circadian clock itself. Once again, the zebrafish has emerged as an excellent model organism with which to explore these specific functional aspects of basic eukaryotic cell biology.