title: Sirt1-deficient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration.
abstract: Hypogonadatropic hypogonadism (HH) can be acquired through energy restriction or may be inherited as congenital hypogonadotropic hypogonadism and its anosmia-associated form, Kallmann's syndrome. Congenital hypogonadotropic hypogonadism is associated with mutations in a group of genes that impact fibroblast growth factor 8 (FGF8) function. The Sirt1 gene encodes a nicotinamide adenine dinucleotide-dependent histone deacetylase that links intracellular metabolic stress to gene expression. Herein Sirt1(-/-) mice are shown to have HH due to failed GnRH neuronal migration. Sirtuin-1 (Sirt1) catalytic function induces GnRH neuronal migration via binding and deacetylating cortactin. Sirt1 colocalized with cortactin in GnRH neurons in vitro. Sirt1 colocalization with cortactin was regulated in an FGF8/fibroblast growth factor receptor-1 dependent manner. The profound effect of Sirt1 on the hormonal status of Sirt1(-/-) mice, mediated via defective GnRH neuronal migration, links energy metabolism directly to the hypogonadal state. Sirt1-cortactin may serve as the distal transducer of neuronal migration mediated by the FGF8 synexpression group of genes that govern HH.
authors.affiliation: Department of Cancer Biology (G.D.S., L.W., C.W., X.J., M.C.C., K.C., T.G.P., I.Y., X.S., M.J.P., R.G.P.) and Sidney Kimmel Cancer Center (G.D.S., L.W., C.W., X.J., M.C.C., K.C., T.G.P., I.Y., X.S., M.J.P., R.G.P.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Translational Research Program in Pediatric Orthopedics (A.D.R.), The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104; Department of Pharmacology (Y.H.), Sapporo Medical University, Sapporo 060-8556, Japan; and Departments of Medicine and Biochemistry (X.H., M.W.M.) and Microbiology and Immunology (X.H., M.W.M.), Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Xuanmiao
authors.initials: X
authors.lastname: Jiao
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Pestell
authors.forename: Ismail
authors.initials: I
authors.lastname: Yaman
authors.forename: Agnese
authors.initials: A
authors.lastname: Di Rocco
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Horio
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Powell
authors.forename: Xiaohong
authors.initials: X
authors.lastname: He
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000107:Acetylation; D000818:Animals; D055162:Biocatalysis; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007006:Hypogonadism / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000473:pathology*; D011485:Protein Binding; D021381:Protein Transport; D051496:Receptor, Fibroblast Growth Factor, Type 1; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000172:deficiency* / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D051356:Cortactin; D007987:Gonadotropin-Releasing Hormone; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D056564:Sirtuin 1