GnRH Neuron-Specific Ablation of Gαq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion

被引：23

作者：

Babwah, Andy V. ^{[1
,2
,3
]}

Navarro, Victor M. ^{[12
,13
]}

Ahow, Maryse ^{[1
,2
,4
]}

Pampillo, Macarena ^{[1
,2
,3
]}

Nash, Connor ^{[6
]}

Fayazi, Mehri ^{[1
,2
,4
]}

Calder, Michele ^{[1
,2
,3
]}

Elbert, Adrienne ^{[1
,2
]}

Urbanski, Henryk F. ^{[8
,9
,10
,11
]}

Wettschureck, Nina ^{[7
]}

Offermanns, Stefan ^{[7
]}

Carroll, Rona S. ^{[12
,13
]}

Bhattacharya, Moshmi ^{[4
,5
]}

Tobet, Stuart A. ^{[6
]}

Kaiser, Ursula B. ^{[12
,13
]}

机构：

[1] Childrens Hlth Res Inst, Victoria Res Labs, London, ON N6C 2V5, Canada

[2] Lawson Hlth Res Inst, London, ON N6A 4V2, Canada

[3] Univ Western Ontario, Dept Obstet & Gynaecol, London, ON N6A 3K7, Canada

[4] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 3K7, Canada

[5] Univ Western Ontario, Dept Oncol, London, ON N6A 3K7, Canada

[6] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA

[7] Max Planck Inst Heart & Lung Res, Dept Pharmacol, D-61231 Bad Nauheim, Germany

[8] Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA

[9] Oregon Natl Primate Res Ctr, Div Reprod & Dev Sci, Beaverton, OR 97006 USA

[10] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA

[11] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA

[12] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

[13] Harvard Univ, Sch Med, Boston, MA 02115 USA

来源：

JOURNAL OF NEUROSCIENCE | 2015年 / 35卷 / 37期

基金：

美国国家卫生研究院; 加拿大自然科学与工程研究理事会;

关键词：

beta-arrestin; GnRH; GnRH secretion; Gq; KISS1R; kisspeptin; PROTEIN-COUPLED RECEPTOR; HORMONE NEURONS; HYPOGONADOTROPIC HYPOGONADISM; PROMOTER TRANSGENICS; DEPENDENT PATHWAY; KISS1(-/-) MICE; GPR54; FERTILITY; MOUSE; EXPRESSION;

D O I：

10.1523/JNEUROSCI.0041-15.2015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 G alpha(q/11)-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r(-/-)) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r(d/d)) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via beta-arrestin, and in mice lacking beta-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of G alpha(q/11) in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that G alpha(q/11)-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes G alpha(q)) was selectively inactivated in the GnRH neurons of global Gna11 (encodes G alpha(11))-null mice by crossing Gnrh-Cre and Gnaq(fl/fl); Gna11(-/-) mice. Experimental Gnaq(fl/fl); Gna11(-/-); Gnrh-Cre (Gnaq(d/d)) and control Gnaq(fl/fl); Gna11(-/-) (Gnaq(fl/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 Gnaq(d/d) mice than in previously characterized Kiss1r(-/-) or Kiss1r(d/d) mice. Additionally, Gnaq(d/d) males were subfertile, and although Gnaq(d/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 Gnaq(d/d) mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect G alpha(q/11)-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice.

引用

页码：12903 / 12916

页数：14