Kisspeptin signalling in the brain: steroid regulation in the rodent and ewe

Abstract

The Kiss1 gene encodes a family of peptides called kisspeptins, which are the natural ligands for the receptor GPR54. In humans and mice, inactivating mutations of GPR54 results in hypogonadotropic hypogonadism, indicating that kisspeptins play a vital role in the regulation of GnRH secretion. In many species, centrally administered kisspeptins stimulate gonadotrophin secretion in a GnRH-dependant manner. Moreover, virtually all GnRH neurons coexpress GPR54. In the hypothalamus, the vast majority of kisspeptin producing cells also express sex steroid receptors, particularly estrogen receptor alpha. Thus, sex steroids are able to directly regulate the expression of Kiss1 mRNA, implicating kisspeptins as the 'missing link' between sex steroid feedback and GnRH secretion. Kiss1-expressing cells are localised to various regions of the forebrain in rodents, primates and sheep. In the arcuate nucleus (ARC) of the rodent and the ewe, sex steroids inhibit the expression of Kiss1 mRNA, suggesting that the kisspeptin secreting neurons here are the conduit for the negative feedback regulation of GnRH secretion. However, in the rodent anteroventral periventricular nucleus (AVPV), sex steroids induce the expression of Kiss1, implying that these kisspeptin neurons play a role in the positive feedback regulation of GnRH secretion. In sheep, there are no Kiss1 neurons in the AVPV and Kiss1 mRNA expression in the ARC is stimulated immediately prior to the preovulatory GnRH/luteinising hormone surge. Thus, kisspeptin neurons in the ARC of the ewe appear well placed to play a role in the negative and positive feedback regulation of GnRH exerted by sex steroids.