title: Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility.
abstract: Hypothalamic kisspeptin neurons integrate and translate cues from the internal and external environments that regulate gonadotropin-releasing hormone (GnRH) secretion and maintain fertility in mammals. However, the intracellular signaling pathways utilized to translate such information into changes in kisspeptin expression, release, and ultimately activation of the kisspeptin-receptive GnRH network have not yet been identified. PI3K is an important signaling node common to many peripheral factors known to regulate kisspeptin expression and GnRH release. We investigated whether PI3K signaling regulates hypothalamic kisspeptin expression, pubertal development, and adult fertility in mice. We generated mice with a kisspeptin cell-specific deletion of the PI3K catalytic subunits p110α and p110β (kiss-p110α/β-KO). Using in situ hybridization, we examined Kiss1 mRNA expression in gonad-intact, gonadectomized (Gdx), and Gdx + steroid-replaced mice. Kiss1 cell number in the anteroventral periventricular hypothalamus (AVPV) was significantly reduced in intact females but not in males. In contrast, compared with WT and regardless of steroid hormone status, Kiss1 cell number was lower in the arcuate (ARC) of kiss-p110α/β-KO males, but it was unaffected in females. Both intact Kiss-p110α/β-KO males and females had reduced ARC kisspeptin-immunoreactive (IR) fibers compared with WT animals. Adult kiss-p110α/β-KO males had significantly lower circulating luteinizing hormone (LH) levels, whereas pubertal development and fertility were unaffected in males. Kiss-p110α/β-KO females exhibited a reduction in fertility despite normal pubertal development, LH levels, and estrous cyclicity. Our data show that PI3K signaling is important for the regulation of hypothalamic kisspeptin expression and contributes to normal fertility in females.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York; Graduate Program in Genetics, Stony Brook University, Stony Brook, New York;
authors.forename: Matthew
authors.initials: M
authors.lastname: Beymer
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York; Graduate Program in Neuroscience, Stony Brook University, Stony Brook, New York;
authors.forename: Ariel L
authors.initials: AL
authors.lastname: Negrón
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York;
authors.forename: Guiqin
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York;
authors.forename: Samuel
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, University of Saarland School of Medicine, Homburg, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Mayer
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York; Institute of Molecular Cardiology, Stony Brook, New York; and Veterans Affairs Medical Center, Northport, New York.
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Toxicology, University of Saarland School of Medicine, Homburg, Germany;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York; Maricedes.acosta@stonybrook.edu.
authors.forename: Maricedes
authors.initials: M
authors.lastname: Acosta-Martínez
mesh_terms: D000818:Animals; D004958:Estradiol / Q000378:metabolism; D030762:Estrous Cycle / Q000235:genetics / Q000502:physiology; D005260:Female; D005298:Fertility / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D059648:Kisspeptins / Q000096:biosynthesis / Q000502:physiology*; D007986:Luteinizing Hormone / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D004958:Estradiol; D007986:Luteinizing Hormone; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose
keywords: fertility; gonadotropins; hypothalamus; kisspeptin; phosphoinositide 3-kinase