Endocrine Abstracts

Activation of the G-protein coupled receptor GPR54 (AXOR12, OT7T175) by peptide ligands (kisspeptins) encoded by the Kiss-1gene is central to acquisition of reproductive competency in mammals. Administration of exogenous kisspeptins stimulates GnRH release from hypothalamic neurons in several species including humans. To confirm that kisspeptins are the natural agonist of GPR54 in vivo and to determine if these ligands have additional physiological functions, we have generated mice with a targetted disruption of the Kiss-1gene. Kiss-1 null mice are viable but fail to undergo sexual maturation at puberty. Mutant female mice do not progress through the oestrus cycle, have thread-like uteri, small ovaries and do not produce mature Graffian follicles. Mutant males have small testes and spermatogenesis arrests mainly at the early haploid spermatid stage. Both sexes have low circulating gonadotrophin (LH and FSH) and sex steroid (β-estradiol or testosterone) hormone levels. Migration of GnRH neurons into the hypothalamus appears normal with appropriate axonal connections to the median eminence and total GnRH content. The hypothalamic-pituitary axis is functional in these mice as shown by robust LH secretion after peripheral administration of kisspeptin-10. These data provide the first direct proof that kisspeptins are the true physiological ligand for the GPR54 receptor in vivo and that loss of Kiss1 cannot be overcome by compensatory mechanisms.