Development And Regulation Of The Luteinizing Hormone Re

黄体生成素的发展与调控

• 批准号: 6671374
• 负责人: SUSAN WRAY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6671374
• 关键词: cell differentiation; cell migration; central nervous system; developmental neurobiology; gamma aminobutyrate; gene expression; gene targeting; genetic regulation; genetically modified animals; gonadotropin releasing factor; human tissue; laboratory mouse; neural cell adhesion molecules; neuroendocrine system; neuronal guidance; neuronal transport; neurons; olfactory lobe; peptide hormone biosynthesis; peripheral nervous system; secretion; tissue /cell culture

LHRH neurons, critical for reproduction, are derived from the nasal placode and migrate into the brain where they become integral members of the hypothalamic-pituitary-gonadal axis. We study mechanism(s) underlying LHRH neuronal differentiation, migration and axonal targeting in normal/transgenic animals, and nasal explants. Intrinsic and trans-synaptic regulation of LHRH gene expression, peptide synthesis and secretion in LHRH neurons are studied using nasal explants, cell lines and normal and transgenic animals. Previous work in our lab 1) showed that outgrowth of olfactory axons and migration of LHRH neurons occur in isolated olfactory pit tissue, 2) revealed olfactory axon 'guidance cues' localized to midline nasal cartilagenous tissue, 3) showed GABA was an important factor in the migration of LHRH neurons in nasal regions and 4) identified a novel gene termed NELF which we hypothesize acts via a homophilic interaction to influence LHRH neuronal migration on olfactory axons. Over the past year, we have continued our work characterizing the expression pattern of NELF during development. NELF is primarily limited to PNS and CNS tissues, being highly expressed in the thalamus both prenatally and postnatally. In addition, we have shown that maturation of LHRH neurons in nasal explants parallels LHRH neurons in vivo, with respect to peptide synthesis and processing and that devoid of CNS tissues LHRH neurons exhibit synchronous neuronal activity. Future studies are directed at the molecules and cues important for development of the olfactory and LHRH neuronal systems as well as the mechanisms regulating LHRH neuronal activity. Specific studies in progress focused on: 1) isolation of midline cues which influence olfactory axon outgrowth; 2) the role of NELF and other molecules in LHRH migration, 3) identifying pacemaker molecules in LHRH neurons that participate in establishment/maintenance of rhythmic activity 4) genes differentially expressed in LHRH neurons as a function of GABAergic stimulation and 5) expression of receptors and channels in LHRH neurons as a function of development.

LHRH 神经元对生殖至关重要，源自鼻基板并迁移到大脑，在那里它们成为下丘脑-垂体-性腺轴的组成部分。我们研究正常/转基因动物和鼻外植体中 LHRH 神经元分化、迁移和轴突靶向的机制。使用鼻外植体、细胞系以及正常和转基因动物研究 LHRH 神经元中 LHRH 基因表达、肽合成和分泌的内在和跨突触调节。我们实验室之前的工作 1) 表明嗅觉轴突的生长和 LHRH 神经元的迁移发生在孤立的嗅坑组织中，2) 揭示了位于中线鼻软骨组织的嗅觉轴突“指导线索”，3) 表明 GABA 是鼻区 LHRH 神经元迁移的重要因素，4) 鉴定了一个称为 NELF 的新基因，我们将其命名为 NELF。 假设通过同质相互作用影响 LHRH 神经元在嗅觉轴突上的迁移。在过去的一年里，我们继续研究表征 NELF 在开发过程中的表达模式。 NELF 主要局限于 PNS 和 CNS 组织，在产前和产后在丘脑中高表达。此外，我们还表明，在肽合成和加工方面，鼻外植体中 LHRH 神经元的成熟与体内 LHRH 神经元平行，并且缺乏 CNS 组织的 LHRH 神经元表现出同步神经元活性。未来的研究将针对对嗅觉和 LHRH 神经元系统发育重要的分子和线索，以及调节 LHRH 神经元活动的机制。正在进行的具体研究集中在：1）影响嗅觉轴突生长的中线线索的分离； 2) NELF 和其他分子在 LHRH 迁移中的作用，3) 识别 LHRH 神经元中参与节律活动建立/维持的起搏分子，4) LHRH 神经元中差异表达的基因作为 GABA 刺激的功能，5) LHRH 神经元中受体和通道的表达作为发育的功能。