HYPOPHYSIOTROPIC NEURON DIFFERENTIATION--TARGET FEEDBACK

描述：拟议的研究旨在检验以下假设 垂体前叶激素作为发育神经营养信号 下丘脑垂体调节(促垂体素)神经元。宽阔的， 这项研究的长期目标是阐明 这些内分泌信号会影响促垂体神经元的存活， 分化，轴突终末引导。这些研究将会进行 利用两种类型的侏儒小鼠进行自发的垂体转录 导致不能产生生长激素(GH)和 催乳素(PRL)，并显示出伴随的神经元异常 产生生长激素调节生长抑素和生长激素释放激素，以及 抑制催乳素的多巴胺。因此，发育过程中信号缺失的影响可能 在没有实验的情况下进行评估，激素治疗可能是有选择性的 而且很具体。总体实验设计为评价 在没有目标反馈的情况下的发展事件，以及 激素替代对这些事件的影响。具体目标是确定，在 幼稚和激素治疗的侏儒鼠，1)在多大程度上 促垂体素轴突异常地终止在脑干外侧或内侧 下丘脑正中隆起(ME)和这种模式是否退行性， 应用顺行和逆行追踪、免疫细胞化学(ICC) 和电子显微镜(EM)，包括轴突引导的评估 ME中的分子和结构元素，2)是否有细胞程序性死亡 生后发生在促垂性多巴胺能神经元中，通过细胞凋亡的ICC 基因产物、核小体末端原位标记和EM，以及3)IGF-I是否 和GDNF分别是生长激素和催乳素效应的中介因子 用原位杂交法表达这些因子及其受体 并测试这两个因素是否可以替代激素替代。 与对调解人的评估有关的是具体目标4，还 定位研究生长激素和催乳素效应的途径和机制 GH和PRL受体，鉴定这些受体所依赖的JAK/STAT蛋白 检测生长激素后即刻早期基因产物的表达 或PRL处理，并鉴定显示受体的神经元表型 或激活，因为促垂体神经元的刺激可能是间接的。

DESCRIPTION: The proposed studies are designed to test the hypothesis that anterior pituitary hormones act as developmental neurotrophic signals for hypothalamic pituitary-regulating (hypophysiotropic) neurons. The broad, long-term objective of the research is to elucidate the mechanisms by which these endocrine signals affect hypophysiotropic neuron survival, differentiation, and axon terminal guidance. The studies will be conducted using two types of dwarf mouse with spontaneous pituitary transcription factor mutations that result in failure to produce growth hormone (GH) and prolactin (PRL), and which show concomitant abnormalities in neurons that produce GH-regulating somatostatin and GH-releasing hormone, and PRL-inhibiting DA. Thus, the effect of absent signal during development may be assessed without experimentation, and hormone treatments may be selective and specific. The general experimental design is evaluation of developmental events in the absence of target feedback, and of effects of hormone replacement on these events. The specific aims are to determine, in naive and hormone-treated dwarf mice, 1) the extent to which hypophysiotropic axons terminate aberrantly outside of or within the hypothalamic median eminence (ME) and whether this pattern is regressive, using anterograde and retrograde tract tracing, immunocytochemistry (ICC) and electron microscopy (EM), including assessment of axonal guidance molecules and structural elements in ME, 2) whether programmed cell death occurs postnatally among hypophysiotropic DA neurons, by ICC of apoptotic gene products, nucleosome end-labeling in situ, and EM, and 3) whether IGF-I and GDNF are respective mediators of GH and PRL effects, by assessing expression of these factors and their receptors using in situ hybridization and testing whether either factor can substitute for hormone replacement. Related to the assessment of mediators is Specific Aim 4, further examination of pathways and mechanisms of GH and PRL effect, by localizing GH and PRL receptors, identifying the JAK/STAT proteins that these receptors activate, measuring the expression of immediate-early gene products after GH or PRL treatment, and identifying the neuronal phenotypes showing receptor or activation, because hypophysiotropic neuron stimulation may be indirect.