Evolution of Peptide Hormones and their Receptors.

摘要

Peptide hormones are critical modulators of physiology and development in humans and have been well characterized for their effects on humans and other mammals. The question of the origin of the many families of peptide hormones in mammals is pressing, as it gives us a window into the evolution of important systems in all extant animals and their common ancestors. The focus of this thesis was to examine the origin of a select group of peptide hormone families including the secretin superfamily, reproductive neuropeptides, insulin and the insulin-like peptides, and stanniocalcin. The evolution of the secretin superfamily was found to have originated with the vertebrates, and new information from the genomes of basal vertebrates like the lamprey Petromyon marinus and elephant shark Callorhinchus milii allows us to better piece together the gene duplications that produced the current hormone family in humans and fish. The reproductive hormones, including gonadotropin-releasing hormone (GnRH), vasopressin/oxytocin, and kisspeptin were examined, with a focus on the evolution of their G protein-coupled receptors. GnRH was found to have originated in the early bilaterians, and its receptors clearly belong to a superfamily also containing receptors of the related neuropeptides adipokinetic hormone and corazonin, which have only been found in protostome invertebrates. Vasopressin/oxytocin receptors share a common ancestor with the GnRH receptors, although their peptides are not structurally related, and evolved at a similar time. Kisspeptin evolved later, within the vertebrates, however its receptors are closely related to an orphan receptor in protostome invertebrates, GPR54, with an unknown ligand. Insulin family members from the tunicate Ciona intestinalis and the amphioxus Branchiostoma floridae were identified, isolated and characterized to determine the nature of the insulin superfamily at the origin of the chordates, and it appears this family was well-developed already. Finally, the calcium-regulator stanniocalcin was identified, isolated and characterized in C. intestinalis and compared with the vertebrate and amphioxus stanniocalcins. A group of stanniocalcins were also discovered in a wide range of both protostomes and unicellular eukaryotes, indicating this ancient group of neurohormones appeared early in eukaryotic evolution.