NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

这是一项更新申请，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。 在目前的支持期间，我们的研究有：a）提供了神经胶质细胞用于调节促黄体激素释放激素（LHRH）神经元的分泌活性的关键信号分子的存在的证据，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等级，以及c）确定了控制女性性发育的下丘脑调节复合体的潜在新成分。 我们现在提出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的方式破坏这些新识别的调控分子的功能，从而测试它们是控制女性生殖能力获得的中央机制的重要组成部分的假设。 为此，提出了以下具体目标：1.检验星形胶质细胞特异性、时间控制的erbB-1受体（介导转化生长因子α（TGF α）的作用）破坏通过影响LHRH释放的性腺非依赖性和类固醇依赖性激活延迟雌性性成熟的假设。 2.研究假设选择性破坏星形胶质细胞erbB-2辅助受体，这是下丘脑erbB-1-和erbB-4-介导的行动，放大时，延迟性成熟的LHRH神经分泌活动的关键阶段的影响。 3.研究星形胶质细胞erbB-4受体（介导下丘脑星形胶质细胞中NRG的作用）的选择性破坏导致与erbB- 1/erbB-2介导的信号丢失相似（或更明显）的成熟缺陷的假设。 4.确定Nel，一个最近发现的具有EGF样重复序列的神经元蛋白，可能在下丘脑控制性发育的细胞间通讯过程中发挥的作用。 5.为了检验以下假设：TTF-1（一种在出生后仍在离散下丘脑区域表达的同源结构域基因Nkx家族成员）是控制女性青春期开始的神经元-神经元和神经胶质-神经元信号传导过程的内在组分。

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.