title: The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic-pituitary gonadotropin signaling.
abstract: Sirtuins (SIRTs) are class-III NAD-dependent histone deacetylases (HDACs) that regulate various physiological processes. Inactivation of SIRT1 in the mouse leads to male sterility, but the molecular mechanisms responsible for this phenotype have not been determined. Here we show that fetal testis development appears normal in Sirt1(-/-) mice. In contrast, the first round of spermatogenesis arrests before the completion of meiosis with abundant apoptosis of pachytene spermatocytes, abnormal Leydig and Sertoli cell maturation, and strongly reduced intratesticular testosterone levels. We show that this phenotype is the consequence of diminished hypothalamic gonadotropin-releasing hormone expression and strongly reduced luteinizing hormone levels. Rather than having an intrinsic effect on male germ cells per se, our results show that SIRT1 regulates spermatogenesis at postnatal stages by controlling hypothalamus-pituitary gonadotropin (HPG) signaling. In addition to its well studied role in control of metabolism and energy homeostasis, our results thus reveal a novel and critical function of SIRT1 in controlling HPG signaling. This phenotype is more severe than those previously described using mice bred on different genetic backgrounds, and highlights the fact that SIRT1 function is strongly modified by other genetic loci.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400 005, India.
authors.forename: Ullas
authors.initials: U
authors.lastname: Kolthur-Seetharam
authors.forename: Katja
authors.initials: K
authors.lastname: Teerds
authors.forename: Dirk G
authors.initials: DG
authors.lastname: de Rooij
authors.forename: Olivia
authors.initials: O
authors.lastname: Wendling
authors.forename: Michael
authors.initials: M
authors.lastname: McBurney
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005298:Fertility / Q000235:genetics* / Q000502:physiology; D006065:Gonadotropins, Pituitary / Q000378:metabolism / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D007248:Infertility, Male / Q000235:genetics* / Q000503:physiopathology; D007985:Leydig Cells / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012708:Sertoli Cells / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D013091:Spermatogenesis / Q000235:genetics; D013739:Testosterone / Q000096:biosynthesis
chemical_list: D006065:Gonadotropins, Pituitary; D013739:Testosterone; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases