Di Sante Gabriele, Wang Liping, Wang Chenguang, Jiao Xuanmiao, Casimiro Mathew C, Chen Ke, Pestell Timothy G, Yaman Ismail, Di Rocco Agnese, Sun Xin, Horio Yoshiyuki, Powell Michael J, He Xiaohong, McBurney Michael W, Pestell Richard G
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.
Mol Endocrinol. 2015 Feb;29(2):200-12. doi: 10.1210/me.2014-1228. Epub 2014 Dec 29.
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.
低促性腺激素性性腺功能减退（HH）可通过能量限制获得，也可能作为先天性低促性腺激素性性腺功能减退及其与嗅觉缺失相关的形式——卡尔曼综合征遗传而来。先天性低促性腺激素性性腺功能减退与一组影响成纤维细胞生长因子8（FGF8）功能的基因突变有关。Sirt1基因编码一种烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，该酶将细胞内代谢应激与基因表达联系起来。在此研究中，Sirt1基因敲除（-/-）小鼠因促性腺激素释放激素（GnRH）神经元迁移失败而出现HH。沉默调节蛋白-1（Sirt1）的催化功能通过结合并使皮层肌动蛋白去乙酰化来诱导GnRH神经元迁移。在体外，Sirt1与皮层肌动蛋白在GnRH神经元中共定位。Sirt1与皮层肌动蛋白的共定位以FGF8/成纤维细胞生长因子受体-1依赖性方式受到调节。Sirt1对Sirt1基因敲除（-/-）小鼠激素状态的深远影响，是通过GnRH神经元迁移缺陷介导的，这将能量代谢直接与性腺功能减退状态联系起来。Sirt1-皮层肌动蛋白可能作为由控制HH的FGF8协同表达基因群介导的神经元迁移的远端转导分子。
