Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron

• Published in: Nature communications 2013, Vol.4 (1), p.2492-2492
• Main Authors: Kirilov, Milen, Clarkson, Jenny, Liu, Xinhuai, Roa, Juan, Campos, Pauline, Porteous, Rob, Schütz, Günther, Herbison, Allan E.
• Format: Article
• Language: English
• Subjects: 631/378/87; 631/443/494/2732/1577; 631/80/86; 692/308; Animals; Female; Fertility - genetics; Gene Expression Regulation, Developmental; Gene Knock-In Techniques; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Humanities and Social Sciences; Hypothalamus - metabolism; Hypothalamus - pathology; Infertility - genetics; Infertility - metabolism; Infertility - pathology; Kisspeptins - genetics; Kisspeptins - metabolism; Mice; Mice, Knockout; multidisciplinary; Neurons - metabolism; Neurons - pathology; Organ Size; Ovary - metabolism; Ovary - pathology; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Kisspeptin-1; Science; Science (multidisciplinary); Sexual Maturation; Signal Transduction
• ISSN: 2041-1723
• DOI: 10.1038/ncomms3492

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. The kisspeptin receptor GPR54 is implicated in the maintenance of mammalian fertility. Kirilov et al. study GPR54 mutant mice and identify a subset of neurons in the brain expressing gonadotropin-releasing hormone as the critical site for kisspeptin action.