Endocrine Abstracts

The Kiss1 gene, originally identified as having anti-metastatic properties encodes several overlapping amidated peptides called kisspeptins. Within the last 5 years, kisspeptin signalling has been shown to also play a crucial role in the initiation of puberty and the maintenance of mammalian fertility by signalling through the G-protein coupled receptor GPR54. Five transgenic mouse lines have been generated with mutations in the Gpr54 gene and two lines with mutations in the Kiss1 gene. The phenotypes of these mutant mice are very similar suggesting no obvious functional compensation by other ligands. The mutant mice are sterile as they fail to undergo puberty and have poor gonadal development and low sex steroid and gonadotrophic hormone levels (hypogonadotrophic hypogonadism). Spermatogenesis and ovulation are severely impaired and mutant females do not show normal oestrous cyclicity. The gonads and the anterior pituitary retain functional responses to hormonal stimulation, however, consistent with the primary defect being a failure to secrete GnRH from the hypothalamus to activate the hypothalamic–pituitary–gonadal axis.

These mutant mice are being used to interrogate the function of GPR54 and kisspeptins in key aspects of mammalian reproduction including the role of these proteins in regulating the neuroendocrine responses of GnRH neurons. Kisspeptin expression is regulated by gonadal steroids (testosterone or oestrogen) and this provides a possible mechanism by which these steroids control GnRH secretion. We have shown that kisspeptin-GPR54 signalling is essential for GnRH neuronal activation and the pre-ovulatory LH surge. We have also shown that kisspeptin can stimulate GnRH secretion by a direct action at GnRH nerve terminals in addition to its likely action at the cell bodies. These mutant mice provide a useful resource to further understand the hypothalamic regulation of mammalian reproduction, its integration with the pituitary–gonadal axis and to study the potential function of Gpr54 and Kiss1 in peripheral tissues.

(Sponsored by Takeda Cambridge and BBSRC Grant BB/C003861/1)