Transgenic mouse models to study Gpr54/kisspeptin physiology

Four transgenic mouse lines have been generated with mutations in the Gpr54 gene and two lines with mutations in the Kiss1 gene. In general, the phenotypes of all these mutant mice are very similar and provide evidence that these molecules constitute an authentic receptor/ligand pair with no obvious redundancy or overlap with other signaling pathways. The mutant mice all fail to undergo pubertal maturation and show poor development of the gonads and infertility with low sex steroid and gonadotrophic hormone levels (hypogonadotrophic hypogonadism). Spermatogenesis and ovulation are severely impaired and mutant females do not show estrous cycling. The gonads and the anterior pituitary retain functional responses to hormonal stimulation however, consistent with the primary defect being a failure to secrete gonadotrophin releasing hormone (GnRH) from the hypothalamus. Slight differences between the phenotype of some of the mutant lines may reflect the type of mutation carried by each line. These mutant mice are being used to interrogate the function of Gpr54 and Kiss1 in key aspects of mammalian reproduction in vivo including the role of these proteins in the generation of the pre-ovulatory luteinizing hormone (LH) surge and aspects of sexual behavior. They 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.