Neuroendocrinology of Puberty and Sexual Development

描述（由申请人提供）：这是一份修订后的更新申请，旨在阐明女性青春期启动的神经内分泌机制。在最后一个资助期间，我们研究了这一假设，即青春期LHRH分泌的激活需要一个细胞间的通信过程中提供的结构和功能连接的神经元和神经胶质细胞亚群的下丘脑。我们也开始测试的假设，神经胶质细胞的双向通信，因此青春期的过程本身，是在转录控制的“上游”调控基因。我们通过以下方式建立了支持这两个概念的初始框架：a）将erbB-1和erbB-4酪氨酸激酶受体定义为神经胶质细胞用于促进LHRH释放的通讯途径的主要组分，B）鉴定离子型/代谢型受体为神经递质能神经元用于协调对LHRH神经元的促进性跨突触和神经胶质输入的信号分子，和c）将同源结构域基因TTF-1定义为参与青春期转录控制的基因上游层次的实例。除了实现这些目标，我们确定了两个新的组成部分的erbB受体介导的神经胶质细胞-神经元双向通信的细胞-细胞信号转导过程的基础，并发现了一个新的基因，可能代表了第二个上游组件的下丘脑调控网络控制女性性发育。我们现在提出的研究，以确定这些新发现的系统在神经内分泌胶质神经元通信的重要性，以及它们可能对女性青春期的启动产生的影响。为此，提出了以下目的：1）验证TACE（一种参与erbB配体和erbB受体的胞外域切割的金属蛋白酶）是兴奋性氨基酸诱导胶质细胞TGF α释放所必需的，因此它对于神经元-胶质细胞介导的青春期控制是重要的假设。2)为了检验SynCAM（一种在erbB-4缺陷小鼠星形胶质细胞中发现水平降低的细胞间粘附分子）的胶质细胞表达参与雌性青春期胶质神经元控制的假设。3)为了验证TTF-1（女性青春期正常时间所需的同源结构域基因）是LHRH分泌青春期激活的神经胶质-神经元相互作用的上游协调者这一假设。4)为了检验一种新的基因，称为EAP-1（增强的AT。青春期-1）与TTF-1沿着属于参与青春期过程转录调节的控制基因的层级。

DESCRIPTION (provided by applicant): This is a revised renewal application aimed at elucidating the neuroendocrine mechanisms underlying the initiation of female puberty. During the last funding period we examined the hypothesis that the activation of LHRH secretion at puberty requires a cell-cell communication process provided by structurally and functionally connected neuronal and glial subsets of the hypothalamus. We also began testing the hypothesis that neuron-glia bidirectional communication, and hence the pubertal process itself, is under the transcriptional control of "upstream" regulatory genes. We established the initial framework supporting both concepts by: a) defining erbB-1 and erbB-4 tyrosine kinase receptors as major components of the communication pathway used by glial cells to facilitate LHRH release, b) identifying ionotropic/metabotropic receptors as signaling molecules used by glutamatergic neurons to coordinate the facilitatory transsynaptic and glial input to LHRH neurons, and c) defining the homeodomain gene TTF-1 as an example of an upstream hierarchy of genes involved in the transcriptional control of puberty. In addition to accomplishing these goals we identified two new components of the cell-cell signaling process underlying erbB receptor-mediated glia-neuron bidirectional communication, and discovered a novel gene that might represent a second upstream component of the hypothalamic regulatory network controlling female sexual development. We now propose studies to define the importance of these newly discovered systems in neuroendocrine glia-neuronal communication and the impact they may exert on the initiation of female puberty. To this end, the following aims are proposed: 1) To test the hypothesis that TACE, a metalloproteinase involved in the ectodomain cleavage of erbB ligands and erbB receptors, is required for excitatory amino acids to induce glial TGFa release, and thus it is important for the neuron-glia mediated control of puberty. 2) To test the hypothesis that glial expression of SynCAM, an intercellular adhesion molecule found at reduced levels in astrocytes of erbB-4-deficient mice, is involved in the glial-neuron control of female puberty. 3) To test the hypothesis that TTF-1, a homeodomain gene required for the normal timing of female puberty, is an upstream coordinator of the glial-neuronal interactions underlying the pubertal activation of LHRH secretion. 4) To examine the hypothesis that a novel gene, termed EAP-1 (Enhanced At. Puberty-1) belongs - along with TTF-1 - to the hierarchy of controlling genes involved in the transcriptional regulation of the pubertal process.