GnRH neuron-specific ablation of G αq/11 results in only partial inactivation of the neuroendocrine-reproductive axis in both male and female mice: In vivo evidence for kiss1r-coupled G αq/11-independent GnRH secretion

Andy V. Babwah, Víctor M. Navarro, Maryse Ahow, Macarena Pampillo, Connor Nash, Mehri Fayazi, Michele Calder, Adrienne Elbert, Henryk F. Urbanski, Nina Wettschureck, Stefan Offermanns, R. S. Carroll, Moshmi Bhattacharya, Stuart A. Tobet, Ursula B. Kaiser

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    14 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)12903-12916
    Number of pages14
    JournalJournal of Neuroscience
    Volume35
    Issue number37
    DOIs
    StatePublished - Sep 16 2015

    Keywords

    • GnRH
    • GnRH secretion
    • Gq
    • KISS1R
    • Kisspeptin
    • β-arrestin

    ASJC Scopus subject areas

    • Neuroscience(all)

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