Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism

Horacio J. Novaira, Momodou L. Sonko, Gloria Hoffman, Yongbum Koo, Chemyong Ko, Andrew Wolfe, Sally Radovick

Research output: Contribution to journalArticle

Abstract

Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron- specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.

Original languageEnglish (US)
Pages (from-to)225-238
Number of pages14
JournalMolecular Endocrinology
Volume28
Issue number2
DOIs
StatePublished - Feb 2014

Fingerprint

Kisspeptins
Hypogonadism
Gonadotropin-Releasing Hormone
Neurons
Periodicity
Puberty
Knockout Mice
Fertility
Cell Membrane
Phenotype
Mutation
Serum

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Novaira, H. J., Sonko, M. L., Hoffman, G., Koo, Y., Ko, C., Wolfe, A., & Radovick, S. (2014). Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. Molecular Endocrinology, 28(2), 225-238. https://doi.org/10.1210/me.2013-1319

Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. / Novaira, Horacio J.; Sonko, Momodou L.; Hoffman, Gloria; Koo, Yongbum; Ko, Chemyong; Wolfe, Andrew; Radovick, Sally.

In: Molecular Endocrinology, Vol. 28, No. 2, 02.2014, p. 225-238.

Research output: Contribution to journalArticle

Novaira, HJ, Sonko, ML, Hoffman, G, Koo, Y, Ko, C, Wolfe, A & Radovick, S 2014, 'Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism', Molecular Endocrinology, vol. 28, no. 2, pp. 225-238. https://doi.org/10.1210/me.2013-1319
Novaira, Horacio J. ; Sonko, Momodou L. ; Hoffman, Gloria ; Koo, Yongbum ; Ko, Chemyong ; Wolfe, Andrew ; Radovick, Sally. / Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 2. pp. 225-238.
@article{1ad56b91064748b3a3f832b65aebb0f2,
title = "Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism",
abstract = "Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron- specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.",
author = "Novaira, {Horacio J.} and Sonko, {Momodou L.} and Gloria Hoffman and Yongbum Koo and Chemyong Ko and Andrew Wolfe and Sally Radovick",
year = "2014",
month = "2",
doi = "10.1210/me.2013-1319",
language = "English (US)",
volume = "28",
pages = "225--238",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "2",

}

TY - JOUR

T1 - Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism

AU - Novaira, Horacio J.

AU - Sonko, Momodou L.

AU - Hoffman, Gloria

AU - Koo, Yongbum

AU - Ko, Chemyong

AU - Wolfe, Andrew

AU - Radovick, Sally

PY - 2014/2

Y1 - 2014/2

N2 - Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron- specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.

AB - Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron- specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.

UR - http://www.scopus.com/inward/record.url?scp=84892505324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892505324&partnerID=8YFLogxK

U2 - 10.1210/me.2013-1319

DO - 10.1210/me.2013-1319

M3 - Article

C2 - 24422632

AN - SCOPUS:84892505324

VL - 28

SP - 225

EP - 238

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 2

ER -