NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

这是一个新的应用，旨在阐明参与控制哺乳动物青春期启动的神经内分泌机制。在目前的支持期内，我们的研究已经提供了证据，证明了神经胶质细胞利用关键信号分子来调节黄体生成素释放激素(LHRH)神经元的分泌活动，b)揭示了控制青春期开始的神经内分泌级联中存在更高水平的层次结构，以及c)发现了控制女性性发育的下丘脑调节复合体中潜在的新成分。我们现在建议使用两种不同的条件基因打靶方法，以细胞特异性和时间受限的方式干扰这些新发现的调节分子的功能，从而检验这一假设，即它们是控制女性生殖能力获得的中枢机制的重要组成部分。为此，我们提出了以下具体目标：1.验证一种假说，即介导转化生长因子α(TGFα)作用的、星形胶质细胞特异性的、时间控制的erbB-1受体的破坏，通过影响性腺非依赖性和类固醇依赖性的LHRH释放来延迟性成熟。2.验证选择性阻断星形胶质细胞erbB-2辅助受体在LHRH神经分泌活动的关键时相中延迟性成熟的假说。3.探讨选择性阻断星形胶质细胞中介导NRGs作用的erbB-4受体可导致类似于(或更明显)由erbB-1/erbB-2介导的信号丢失所引起的成熟缺陷的假说。4.确定NEL，一种新近发现的具有EGF样重复序列的神经元蛋白，在下丘脑性发育控制性发育的细胞间通讯过程中可能发挥的作用。5.验证如下假设：TTF-1是Nkx同源结构域基因家族的成员，在出生后仍在下丘脑的离散区域表达，是控制女性青春期开始的神经元到神经元和胶质细胞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.