Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron.
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.
Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Milen
M
Kirilov
Jenny
J
Clarkson
Xinhuai
X
Liu
Juan
J
Roa
Pauline
P
Campos
Rob
R
Porteous
Günther
G
Schütz
Allan E
AE
Herbison
D000818:Animals; D005260:Female; D005298:Fertility / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D007246:Infertility / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D012741:Sexual Maturation; D015398:Signal Transduction
C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone