Neuroendocrinology of Puberty and Sexual Development

描述(申请人提供)：这是一份修订后的续期申请，旨在阐明女性青春期启动的神经内分泌机制。在上一次资助期间，我们检验了一种假设，即青春期LHRH分泌的激活需要一个由下丘脑的结构和功能连接的神经元和神经胶质亚群提供的细胞-细胞通信过程。我们还开始测试这一假设，即神经元-神经胶质双向通讯，因此青春期过程本身，是在“上游”调控基因的转录控制下。我们通过以下方法建立了支持这两个概念的初步框架：a)将erbB-1和erbB-4酪氨酸激酶受体定义为神经胶质细胞用来促进LHRH释放的通讯途径的主要组成部分，b)将离子/代谢性受体确定为谷氨酸能神经元用来协调易化性跨突触和神经胶质输入到LHRH神经元的信号分子，以及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一个例子。除了实现这些目标外，我们还发现了两个新的细胞-细胞信号传递过程的组成部分，这些信号传递过程支撑着erbB受体介导的胶质细胞-神经元双向通讯，并发现了一个新的基因，它可能代表控制女性性发育的下丘脑调控网络的第二个上游组成部分。我们现在建议进行研究，以确定这些新发现的系统在神经内分泌神经胶质细胞-神经元通讯中的重要性，以及它们可能对女性青春期的启动产生的影响。为此，我们提出了以下目标：1)验证这样一种假说，即兴奋性氨基酸诱导神经胶质细胞TGFa的释放对于神经元-神经胶质细胞介导的青春期控制非常重要。TACE是一种参与erbB配体和erbB受体胞外切割的金属蛋白酶。2)验证一种细胞间黏附分子SynCAM的胶质细胞表达是否参与了女性青春期神经胶质细胞的调控。3)验证TTF-1是女性青春期正常发育所必需的同源结构域基因，是青春期激活LHRH分泌的神经胶质-神经元相互作用的上游协调者。4)验证一种新基因，称为EAP-1(EnhancedAt.青春期-1)和TTF-1一样，属于参与青春期过程转录调控的控制基因的层次。

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.