DEVELOPMENT AND REGULATION OF THE LUTEINIZING HORMONE RELEASING HORMONE SYSTEM

LHRH神经元对生殖至关重要， 源自嗅板并迁移到大脑， 在那里他们成为 下丘脑垂体性腺轴我们研究机制（S） 在正常/转基因动物中潜在的LHRH神经元迁移， 和鼻移植物。LHRH的内在和跨突触调节 胚胎中的基因表达、肽合成和分泌 LHRH神经元（CNS外）与出生后LHRH神经元 (in CNS）使用鼻外植体和器官型 文化，分别。LHRH神经元表达GABA受体， GABA能神经元存在于鼻区。体外迁移 的LHRH神经元：a）抑制GABA激动剂，B）增加 GABA拮抗剂和河豚毒素治疗。我们 假设GABA能信号调节进入时间 进入中枢神经系统研究N的作用- 糖基化对LHRH发育的影响，我们发现衣霉素 治疗显著改变了嗅觉轴突的生长， 在嗅窝（OP）之间穿行的纤维，而不是离开 在到达中线组织时取出。尽管由于 嗅觉轴突发生变化，治疗没有破坏嗅觉轴突的联系。 LHRH神经元及其轴突通路，也没有LHRH的运动 神经元的OP，表明分子机制（S） 这些事件的基础是独立的N-糖基化。 中线/OP关系的操作证实了导航 表达用于嗅觉轴突适当定位的信号 软骨中线组织研究动脉瘤性 基因表达、生物合成和分泌之间的关系， 多巴胺能神经元和LHRH的mRNA更新率 神经元酪氨酸羟化酶（TH; DA标志物） 神经元）mRNA周转率之间发现下丘脑 DA群体，弓状神经元显示TH mRNA 周转率（6-7小时），对应于已知的节奏 这些神经元的输出。LHRH神经分泌是 搏动（约1小时）。为了保持这种脉动的轮廓，我们 假设LHRH mRNA迅速衰减。我们确定 LHRH mRNA快速衰减（5-13分钟）， 衰减速率慢得多（329-344分钟）。值得注意的是， LHRH mRNA的表达速率对应于LHRH的快速衰减速率 脉搏通过比较哺乳动物LHRH mRNA的3 'UTR， 确定了两个保守的区域，这可能涉及在 观察周转动力学。目前，我们正在确定：1） 影响嗅轴突生长的中线线索; 2） LHRH神经元与 它们的轴突通路; 3）在神经元中选择性表达的基因， 迁移性LHRH神经元; 4）甘丙肽表达细胞之间的关系 LHRH神经元的分化和/或迁移; 5） 与LHRH mRNA快速周转相关的因素。

LHRH neurons, critical for reproduction, are derived from the olfactory placode and migrate into the brain, where they become integral members of the hypothalamic-pituitary-gonadal axis. We study mechanism(s) underlying LHRH neuronal migration in normal/transgenic animals, and nasal explants. Intrinsic and trans-synaptic regulation of LHRH gene expression, peptide synthesis and secretion in embryonic LHRH neurons (outside the CNS) versus postnatal LHRH neurons (in the CNS) is studied using nasal explants and organotypic cultures, respectively. LHRH neurons express GABA receptors and GABAergic neurons are present in nasal regions. In vitro, migration of LHRH neurons is: a) inhibited by a GABA agonist, b) increased by GABA antagonists and treatment with tetrodotoxin. We hypothesize that GABAergic signals regulate the timing of entrance of LHRH neurons into the CNS. Examining the role of N- glycosylation on LHRH development, we found that tunicamycin treatment dramatically altered olfactory axon outgrowth - with fibers traversing between olfactory pits (OP), instead of exiting the explant upon reaching midline tissue. Although outgrowth of olfactory axons changed, treatment did not disrupt association of LHRH neurons with their axonal pathway, nor movement of LHRH neurons from the OP, indicating that the molecular mechanism(s) underlying these events is independent of N- gycosylation. Manipulations of midline/OP relation confirmed that a navigational signal(s) for appropriate positioning of olfactory axons is expressed by cartilagenous midline tissue. To investigate the relationship between gene expression, biosynthesis and secretion, we examined mRNA turnover rates in dopaminergic (DA) neurons and LHRH neurons. Differences in tyrosine hydroxlase (TH; marker of DA neurons) mRNA turnover rates were found between hypothalamic DA populations, with arcuate neurons exhibiting a TH mRNA turnover rate (6-7 hr) which corresponded to the known rhythmic output displayed by these neurons. LHRH neurosecretion is pulsatile (about 1 hr ). To maintain this pulsatile profile, we hypothesized that LHRH mRNA rapidly decays. We determined that there is a fast decay of LHRH mRNA (5-13 min), followed by a much slower decay rate (329-344 min). Notably, the rapid decay rate of LHRH mRNA corresponds to the rapid decay rate of LHRH pulses. By comparing the 3'UTR of mammalian LHRH mRNAs, we identified two conserved regions which may be involved in the observed turnover kinetics. Currently, we are determining: 1) the midline cues which influence olfactory axon outgrowth; 2) the molecular nature of the interaction between LHRH neurons and their axonal pathway; 3) genes which are selectively expressed in migrating LHRH neurons; 4) the relation of galanin expressing cells to the differentiation and/ or migration of LHRH neurons and; 5) factors related to rapid LHRH mRNA turnover.