Figure 7.

A summary schema showing the evolution of CRF and urocortins hormones and their functions. Diuretic hormones (DH44) and DH44 receptors in the fruit flies probably served as prototypes for urocortin 3 and 2, and CRF receptors, respectively, which first appeared in Actinoptergyii (fish) and Sarcoptergyii after a genome-wide duplication event nearly 400 million years ago. Distinct CRF, urotensin I (UI), urocortins, and sauvagine peptides first seemed to have appeared nearly 500 million years ago. The innervation of hypothalamic cells by CRF family members occurred in class Actinoptergyii along with appearance of urocortin-like peptides. The release of CRF into the portal circulation appeared in Sarcoptergyii, whereas UI-like and sauvagine peptides transitioned to being expressed in the skin in the amphibians. The innervation and descending of CRF fibers in the spinal cord seemed to have occurred nearly 290 million years ago [2]. As the peptides evolved, the functions appeared to have diversified to include osmo and vasoregulation, as well as regulation of HPA axis-mediated stress responses. By virtue of having sex hormone response elements in the promoter regions of all four hormones and two receptors, sex-specific differences in the expression and function mediated by the CRF system are noted.