RT Journal Article
SR Electronic
T1 GnRH Neuron-Specific Ablation of Gα<sub>q/11</sub> Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: <em>In Vivo</em> Evidence for Kiss1r-Coupled Gα<sub>q/11</sub>-Independent GnRH Secretion
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12903
OP 12916
DO 10.1523/JNEUROSCI.0041-15.2015
VO 35
IS 37
A1 Andy V. Babwah
A1 Víctor M. Navarro
A1 Maryse Ahow
A1 Macarena Pampillo
A1 Connor Nash
A1 Mehri Fayazi
A1 Michele Calder
A1 Adrienne Elbert
A1 Henryk F. Urbanski
A1 Nina Wettschureck
A1 Stefan Offermanns
A1 Rona S. Carroll
A1 Moshmi Bhattacharya
A1 Stuart A. Tobet
A1 Ursula B. Kaiser
YR 2015
UL http://www.jneurosci.org/content/35/37/12903.abstract
AB 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 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 lacking β-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-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gαq) 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/d mice 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.SIGNIFICANCE STATEMENT The 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.