GnRH Neuron-Specific Ablation of Gαq/11Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice:In VivoEvidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion
Authors: Babwah Andy V. , Navarro Víctor M. , Ahow Maryse , Pampillo Macarena , Nash Connor , Fayazi Mehri , Calder Michele , Elbert Adrienne , Urbanski Henryk F. , Wettschureck Nina , Offermanns Stefan , Carroll Rona S. , Bhattacharya Moshmi , Tobet Stuart A. , Kaiser Ursula B. 
Published: September 2015

The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion ofKiss1r(Kiss1r−/−) or a GnRH neuron-specific deletion ofKiss1r(Kiss1rd/d) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this,Gnaq(encodes Gαq) was selectively inactivated in the GnRH neurons of globalGna11(encodes Gα11)-null mice by crossingGnrh-CreandGnaqfl/fl;Gna11−/−mice. ExperimentalGnaqfl/fl;Gna11−/−;Gnrh-Cre(Gnaqd/d) and controlGnaqfl/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 inGnaqd/dmice than in previously characterizedKiss1r−/−orKiss1rd/dmice. Additionally,Gnaqd/dmales were subfertile, and althoughGnaqd/dfemales 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 inGnaqd/dmice. 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 inGnaqd/dmice.

SIGNIFICANCE STATEMENTThe gonadotropin-releasing hormone (GnRH) is the master regulator of fertility. Over the last decade, several studies have established that the KISS1 receptor, KISS1R, is a potent trigger of GnRH secretion and inactivation of KISS1R on the GnRH neuron results in infertility. While KISS1R is best understood as a Gαq/11-coupled receptor, we previously demonstrated that it could couple to and signal via non-Gαq/11-coupled pathways. The present study confirms these findings and, more importantly, while it establishes Gαq/11-coupled signaling as a major conduit of GnRH secretion, it also uncovers a significant role for non-Gαq/11-coupled signaling in potentiating reproductive development and function. This study further suggests that by augmenting signaling via these pathways, GnRH secretion can be enhanced to treat some forms of infertility.