The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger ofGnRHsecretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r-/-) or a GnRH neuron-specific deletion of Kiss1r (Kiss1rd/d) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lackingβ-arrestin-1 or-2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independentGnRHsecretion would be sufficient to maintain fertility. To test this, Gnaq (encodesGaq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα11)-null mice by crossing Gnrh-Cre and Gnaqfl/fl;Gna11-/-mice. Experimental Gnaqfl/fl;Gna11-/-Gnrh-Cre (Gnaqd/d) and control Gnaqfl/fl;Gna11-/-(Gnaqfl/fl) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaqd/dmice than in previously characterized Kiss1r-/-or Kiss1rd/d mice. Additionally, Gnaqd/d males were subfertile, and although Gnaqd/d females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaqd/d mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gαq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaqd/d mice.
- GnRH secretion
ASJC Scopus subject areas