RESUMEN

Signaling between kisspeptin and its receptor, G-protein-coupled receptor 54 (Gpr54), is now recognized as being essential for normal fertility. However, the key cellular location of kisspeptin-Gpr54 signaling is unknown. Here we create a mouse with a GnRH neuron-specific deletion of Gpr54 to assess the role of gonadotropin-releasing hormone (GnRH) neurons. Mutant mice are infertile, fail to go through puberty and exhibit markedly reduced gonadal size and follicle-stimulating hormone levels alongside GnRH neurons that are unresponsive to kisspeptin. In an attempt to rescue the infertile phenotype of global Gpr54⁻/⁻ mutants, we use BAC transgenesis to target Gpr54 to the GnRH neurons. This results in mice with normal puberty onset, estrous cyclicity, fecundity and a recovery of kisspeptin's stimulatory action upon GnRH neurons. Using complimentary cell-specific knockout and knockin approaches we demonstrate here that the GnRH neuron is the key site of kisspeptin-Gpr54 signaling for fertility.

Asunto(s)

Hormona Liberadora de Gonadotropina/genética , Hipotálamo/metabolismo , Infertilidad/genética , Kisspeptinas/genética , Neuronas/metabolismo , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Animales , Femenino , Fertilidad/genética , Regulación del Desarrollo de la Expresión Génica , Técnicas de Sustitución del Gen , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/patología , Infertilidad/metabolismo , Infertilidad/patología , Kisspeptinas/metabolismo , Ratones , Ratones Noqueados , Neuronas/patología , Tamaño de los Órganos , Ovario/metabolismo , Ovario/patología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Kisspeptina-1 , Maduración Sexual