Sirt1-Deficient Mice Have Hypogonadotropic Hypogonadism due to Defective GnRH Neuronal Migration
Sirt1-Deficient Mice Have Hypogonadotropic Hypogonadism due to Defective GnRH Neuronal Migration
复制标题
DOI：
10.1210/me.2014-1228
复制
发表时间：
2015-02-01
影响因子：
--
通讯作者：
Pestell, Richard G.
中科院分区：
文献类型：
--
作者：
Di Sante, Gabriele;Wang, Liping;Pestell, Richard G.
低促性腺激素性性腺功能减退症（HH）可以通过能量限制获得，也可以遗传为先天性低促性腺激素性性腺功能减退症及其嗅觉缺失相关形式，卡尔曼综合征。先天性低促性腺激素性腺功能减退症与一组影响成纤维细胞生长因子8（FGF 8）功能的基因突变有关。Sirt 1基因编码烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，其将细胞内代谢应激与基因表达联系起来。在本文中，Sirt 1（-/-）小鼠显示由于GnRH神经元迁移失败而具有HH。Sirtuin-1（Sirt 1）的催化功能通过结合和脱乙酰化coronin诱导GnRH神经元迁移。Sirt 1与coronin共定位于体外培养的GnRH神经元。Sirt 1与coronin的共定位以FGF 8/成纤维细胞生长因子受体-1依赖的方式调节。Sirt 1对Sirt 1（-/-）小鼠激素状态的深远影响，通过有缺陷的GnRH神经元迁移介导，将能量代谢直接与性腺功能减退状态联系起来。Sirt 1-coronin可能作为远端的传感器的神经元迁移介导的FGF 8 synexpression组的基因，管理HH。
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.