Neuroendocrinology of Puberty and Sexual Development

描述（由申请人提供）：这是一份修订后的续期申请，旨在阐明女性青春期开始的神经内分泌机制。在上一个资助期，我们检验了青春期LHRH分泌的激活需要一个由下丘脑结构和功能连接的神经元和胶质亚群提供的细胞间通讯过程的假设。我们也开始测试神经元-神经胶质双向交流的假设，因此青春期过程本身是在“上游”调节基因的转录控制下。我们通过以下方式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促进LHRH释放的通讯途径的主要成分，b)将嗜离子/代谢受体定义为谷氨酸能神经元使用的信号分子，以协调对LHRH神经元的促进性跨突触和胶质输入，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上游基因层次的一个例子。除了完成这些目标外，我们还发现了erbB受体介导的胶质神经元双向交流的细胞-细胞信号传导过程的两个新组成部分，并发现了一个可能代表下丘脑调控网络控制女性性发育的第二个上游组成部分的新基因。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胶质-神经元通讯中的重要性，以及它们可能对女性青春期开始产生的影响。为此，本研究提出以下目标：1)验证TACE（一种参与erbB配体和erbB受体外结构域切割的金属蛋白酶）是兴奋性氨基酸诱导胶质细胞TGFa释放所必需的，因此它在神经元-胶质细胞介导的青春期控制中起重要作用。2)验证在erbb -4缺陷小鼠星形胶质细胞中发现的细胞间粘附分子SynCAM的胶质表达水平降低，参与了女性青春期的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分泌青春期激活的胶质-神经元相互作用的上游协调者的假设。4)检验一种被称为EAP-1 （Enhanced At）的新基因的假设。青春期-1)与TTF-1一样，属于控制青春期过程转录调节的基因等级。

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.