Ancient evolution of stress-regulating peptides in vertebrates

Recent studies on genomic sequences have led to the discovery of novel corticotropin-releasing factor (CRF) type 2 receptor-selective agonists, stresscopin (SCP)/urocortin III (UcnIII), and stresscopin-related peptide (SRP)/urocortin II (UcnII). In addition, analyses of vertebrate genomes showed that the CRF peptide family includes four distinct genes, CRF, urocortin/urotensin I, SCP/UcnIII, and SRP/UcnII. Each of these four genes is highly conserved during evolution and the identity between mammalian and teleost orthologs ranges from >96% for CRF to >55% for SCP. Phylogenetic studies showed that the origin of each of these peptides predates the evolution of tetrapods and teleosts, and that this family of peptide hormones evolved from an ancestor gene that developed the CRF/urocortin and SCP/SRP branches through an early gene duplication event. These two ancestral branches then gave rise to additional paralogs through a second round of gene duplication. Consequently, each of these peptides participates in the regulation of stress responses over the 550 million years of vertebrate evolution. The study also suggested that the fight-or-flight and stress-coping responses mediated mainly by CRF types 1 and 2 receptors evolved early in chordate evolution. In addition, we hypothesize that the CRF/CRF receptor signaling evolved from the same ancestors that also gave rise to the diuretic hormone/diuretic hormone receptors in insects. Thus, a complete inventory of CRF family ligands and their receptors in the genomes of different organisms provides an opportunity to reveal an integrated view of the physiology and pathophysiology of the CRF/SCP family peptides, and offers new insights into the evolution of stress regulation in vertebrates.