NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT

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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.