The zebrafish stress axis: molecular fallout from the teleost-specific genome duplication event

The teleost-specific whole genome duplication event 350 million years ago resulted in a variety of duplicated genes that exist in fish today. In this review, we examine whether molecular components involved in the functioning of the hypothalamus-pituitary-interrenal (HPI) axis are present as single or duplicate genes. Specifically, we looked at corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and the glucocorticoid receptor (GR). The focus is on zebrafish but a variety of species are covered whenever data is available through literature or genomic database searches. Duplicate CRH genes are retained in the salmoniformes and cypriniformes, and the peptide sequences are very similar or identical. Zebrafish, along with the Acanthopterygii, are the exceptions as they have a single CRH gene. Also, two copies of the proopiomelanocortin (POMC) gene, which encodes for ACTH and other peptides, have been observed in all teleosts except tilapia and sea bass. In zebrafish, ACTH is derived from only one POMC gene, since the cleavage site is mutated in the other gene. All teleosts examined to date have two GRs, including the recent discoveries of duplicate GRs in two species of cyprinids (carp and fathead minnow). Zebrafish are the only known exception with one GR gene. The loss of duplicate genes is not a general feature of the zebrafish genome, but zebrafish have lost the duplicate CRH, ACTH and GR genes in the past 33 million years, after possessing two of each for the previous 300 million years. The evolutionary pressures underlying the rapid loss of these HPI axis genes, and the implications on the development and the functioning of the evolutionarily conserved cortisol stress response in zebrafish are currently unknown.