NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

这是一个更新的应用程序，旨在阐明参与控制哺乳动物青春期开始的神经内分泌机制。在目前的支持期内，我们的研究已经：a)为神经胶质细胞调节黄体生成素释放激素（LHRH）神经元分泌活性的关键信号分子的存在提供了证据；b)揭示了在控制青春期开始的神经内分泌级联中存在更高层次的层次；c)发现了控制女性性发育的下丘脑调节复合体的潜在新成分。我们现在建议使用两种不同的条件基因靶向方法，以细胞特异性和时间限制性的方式破坏这些新认识的调节分子的功能，从而验证它们是控制女性生殖能力获得的中心机制的重要组成部分的假设。为此，提出以下具体目标：为了验证星形胶质细胞特异性的，暂时控制的erbB-1受体的破坏，介导转化生长因子α (TGFalpha)的作用，通过影响性腺独立和类固醇依赖的LHRH释放激活来延迟女性性成熟的假设。2. 为了验证选择性破坏星形胶质erbB-2共受体的假设，这是下丘脑erbb -1和erbb -4介导的作用放大所必需的，当在LHRH神经分泌活性的关键阶段受到影响时，会延迟性成熟。3. 研究选择性破坏星形胶质erbB-4受体（在下丘脑星形胶质细胞中介导NRGs的作用）导致与erbB- 1/erbB-2介导的信号缺失类似（或更明显）的成熟缺陷的假设。4. 为了确定Nel（一种最近发现的具有egf样重复序列的神经元蛋白）在下丘脑控制性发育的细胞间通讯过程中可能发挥的作用。5. TTF-1是Nkx同源结构域基因家族的一员，在出生后仍在下丘脑离散区域表达，是控制女性青春期开始的神经元到神经元和胶质到神经元信号过程的内在组成部分。

This is a renewal application aimed at elucidating the neuroendocrine mechanisms involved in controlling the initiation of mammalian puberty. During the current period of support, our studies have: a) provided evidence for the existence of key signaling molecules utilized by glial cells to regulate the secretory activity of luteinizing hormone releasing hormone (LHRH) neurons, b) unveiled the existence of a higher level of hierarchy in the neuroendocrine cascade that controls the onset of puberty and c) identified a potential new component of the hypothalamic regulatory complex controlling females sexual development. We now propose the use of two different conditional gene targeting approaches to disrupt the function of these newly recognized regulatory molecules in a cell-specific and temporally-restricted manner, and thus, test the hypothesis that they are essential components of the central mechanism controlling the acquisition of female reproductive capacity. To this end, the following specific aims are proposed: 1. To test the hypothesis that an astrocyte-specific, temporally-controlled disruption of erbB-1 receptors, which mediate the actions of transforming growth factor alpha (TGFalpha), delays female sexual maturation by affecting both the gonadal-independent and steroid- dependent activation of LHRH release. 2. To examine the hypothesis that selective disruption of astroglial erbB-2 coreceptors, which are required for amplification of hypothalamic erbB-1-and erbB-4-mediated actions, delays sexual maturation when effected at key phases of LHRH neurosecretory activity. 3. To investigate the hypothesis that selective disruption of astroglial erbB-4 receptors, which mediate the actions of NRGs in hypothalamic astrocytes, results in maturational deficits similar to (or more pronounced than) those caused by the loss of erbB- 1/erbB-2-mediated signaling. 4. To define the role that Nel, a recently identified neuronal protein with EGF-like repeats, may play in the cell-cell communication process underlying the hypothalamic control of sexual development. 5. To test the hypothesis that TTF-1, a member of the Nkx family of homeodomain genes that remains postnatally expressed in discrete hypothalamic regions, is an intrinsic component of both the neuron-to-neuron and glia-to-neuron signaling process controlling the onset of female puberty.