Development And Regulation Of The Luteinizing Hormone Re

黄体生成素的发展与调控

• 批准号: 6503235
• 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/6503235
• 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. We hypothesize NELF 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. We have worked throughout the year to generate a NELF knockout and currently have chimeric animals that are being bred. Future studies are directed at understanding the role of NELF during development and the downstream signals activated by this molecule that result in axon outgrowth and cell movement. To understand the regulation of LHRH neurons and their cellular responses, we examined the activity of LHRH neurons in nasal explants. We found that there are important maturational events that are intrinsic properties of these cells such as biosynthesis of peptide product. We have also demonstrated that LHRH neurons maintained in vitro can release LHRH peptide and rapidly synthesize new peptide in response to a secretory event. Work in progress is focused on: 1) isolation of the midline cues which influence olfactory axon outgrowth; 2) the role of NELF and other molecules in LHRH migration, 3) whether LHRH neurons maintained in nasal explants (devoid of brain influences) show rhythmic activity patterns and if so the mechanisms underlying this rhythm, and 4) genes differentially expressed in LHRH neurons as a function of GABAergic stimulation.

LHRH神经元，生殖的关键，是从鼻基板和迁移到大脑，在那里他们成为下丘脑-垂体-性腺轴的组成部分。我们在正常/转基因动物和鼻外植体中研究LHRH神经元分化、迁移和轴突靶向的潜在机制。利用鼻外植体、细胞系以及正常和转基因动物研究了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。本实验室的前期工作1）发现在离体的嗅窝组织中存在嗅轴突的生长和LHRH神经元的迁移; 2）发现嗅轴突的“引导线索”定位于中线鼻软骨组织; 3）发现GABA是LHRH神经元在鼻区迁移的重要因素; 4）鉴定了一个新的基因NELF。我们假设NELF通过嗜同性相互作用影响LHRH神经元迁移到嗅觉轴突。在过去的一年中，我们继续我们的工作，表征NELF在发育过程中的表达模式。NELF主要局限于PNS和CNS组织，在出生前和出生后的丘脑中高度表达。我们一整年都在努力产生NELF敲除，目前正在培育嵌合动物。未来的研究旨在了解NELF在发育过程中的作用以及由该分子激活的导致轴突生长和细胞运动的下游信号。为了了解LHRH神经元及其细胞反应的调节，我们检测了鼻外植体中LHRH神经元的活性。我们发现这些细胞具有重要的成熟事件，如肽产物的生物合成。我们还证明了体外培养的LHRH神经元可以释放LHRH肽并快速合成新的肽以响应分泌事件。正在进行的工作集中在：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）保持在鼻外植体中的LHRH神经元（无脑影响）是否显示节律性活动模式，如果是这样，这种节律的机制; 4）在LHRH神经元中差异表达的基因作为GABA能刺激的功能。