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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Winer, Karen
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Oregon Health and Science University
Schools of Medicine
United States
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Lomniczi, Alejandro; Loche, Alberto; Castellano, Juan Manuel et al. (2013) Epigenetic control of female puberty. Nat Neurosci 16:281-9
Lomniczi, Alejandro; Wright, Hollis; Castellano, Juan Manuel et al. (2013) A system biology approach to identify regulatory pathways underlying the neuroendocrine control of female puberty in rats and nonhuman primates. Horm Behav 64:175-86
Dissen, Gregory A; Lomniczi, Alejandro; Heger, Sabine et al. (2012) Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology 153:350-61
Matagne, V; Kim, J G; Ryu, B J et al. (2012) Thyroid transcription factor 1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression. J Neuroendocrinol 24:916-29
Mueller, Johanna K; Koch, Ines; Lomniczi, Alejandro et al. (2012) Transcription of the human EAP1 gene is regulated by upstream components of a puberty-controlling Tumor Suppressor Gene network. Mol Cell Endocrinol 351:184-98
Dissen, G A; Lomniczi, A; Boudreau, R L et al. (2012) Targeted gene silencing to induce permanent sterility. Reprod Domest Anim 47 Suppl 4:228-32
Sandau, Ursula S; Alderman, Zefora; Corfas, Gabriel et al. (2012) Astrocyte-specific disruption of SynCAM1 signaling results in ADHD-like behavioral manifestations. PLoS One 7:e36424
Sandau, Ursula S; Mungenast, Alison E; McCarthy, Jack et al. (2011) The synaptic cell adhesion molecule, SynCAM1, mediates astrocyte-to-astrocyte and astrocyte-to-GnRH neuron adhesiveness in the mouse hypothalamus. Endocrinology 152:2353-63
Yeung, Kay T; Das, Sharmistha; Zhang, Jin et al. (2011) A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2. Mol Cell Biol 31:2287-98
Sandau, Ursula S; Mungenast, Alison E; Alderman, Zefora et al. (2011) SynCAM1, a synaptic adhesion molecule, is expressed in astrocytes and contributes to erbB4 receptor-mediated control of female sexual development. Endocrinology 152:2364-76

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