Gonadotropin-releasing hormone (GnRH) drives the hypothalamic-pituitary-gonadal axis. The GnRH neurons have an extraordinary origin. In the mouse, they arise in the presumptive vomeronasal organ within the olfactory placode at e11.5. As they differentiate, they migrate past the cribriform plate, through the olfactory bulb and into the hypothalamus, finally extending their axons to the median eminence. This discrete population of ~800 neurons, scattered through the hypothalamus, controls puberty, menstrual cyclicity, fertility, and meno- pause. Disrupted migration or disregulated secretion results in failures in puberty, fertility, and reproductive function. The overall goal of this renewal application is to elucidate the molecular, epigenetic, and developmental mechanisms that regulate hypothalamic GnRH neuron migration and maturation. We will utilize two major model systems: our immortalized GnRH-secreting hypothalamic cells (GT1) and genetically modified mice. Under the support of this long-standing grant, we have identified evolutionarily conserved promoter and enhancer regions that target GnRH gene expression exclusively to cultured GT1 cells in vitro and to GnRH neurons in vivo. We have shown that these GnRH regulatory regions are controlled by transcriptional regulators: Oct1, NF1, Gata4, Otx2, Pbx, Prep, Meis, Dlx, Msx, necdin, C/EBP?, Six6/3, and the TLE (Grg) co- repressors, and that mouse models lacking any one of a number of these fail to produce the correct population of GnRH neurons and/or disrupt migration in vivo. For this renewal application, we propose three novel aims:
Aim 1 will address the differentiation and maturation of the GnRH neuron during migration determining the fate of neurons that lack expression of factors in the Dlx/Msx/Necdin pathway, and elucidate the mechanism of Msx repression of GnRH gene expression.
Aim 2 will focus on specific homeodomain factors crucial for the development of the hypothalamus as a whole and determine their role in GnRH neuron migration and maturation in vivo and in vitro.
Aim 3 will address the fundamental mechanisms of the neuron-specific enhancers of the GnRH gene. We have discovered that the major enhancer critical for neuron-specific GnRH expression is bound by activated Polymerase II and is transcribed into RNA. This long, noncoding RNA will be characterized in vitro and in vivo and its mechanisms of action will be determined. The homologous enhancers in human will be analyzed and screened for mutations in hypogonadal patient DNA. Our overarching hypothesis is that developmental migration and maturation of the GnRH neuron require the acquisition of a transcriptional regulatory program that relies on developmental coordination of homeodomain transcription factors and long non-coding enhancer RNA. We believe these studies will provide valuable insight into novel regulatory mechanisms and enable progression beyond the currently accepted paradigms. This multifaceted approach should yield a comprehensive understanding of the program of GnRH neuronal migration and cell fate in vivo and in vitro and provide insight into the genetics of hypogonadotropic hypogonadism.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Lamar, Charisee A
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University of California San Diego
Obstetrics & Gynecology
Schools of Medicine
La Jolla
United States
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Pandolfi, Erica C; Hoffmann, Hanne M; Schoeller, Erica L et al. (2018) Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration. Mol Neurobiol 55:8709-8727
Hoffmann, Hanne M; Gong, Ping; Tamrazian, Anika et al. (2018) Transcriptional interaction between cFOS and the homeodomain-binding transcription factor VAX1 on the GnRH promoter controls Gnrh1 expression levels in a GnRH neuron maturation specific manner. Mol Cell Endocrinol 461:143-154
Hoffmann, Hanne; Pandolfi, Erica; Larder, Rachel et al. (2018) Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2, Causes Subfertility in Mice Via Distinct Mechanisms. Neuroendocrinology :
Xie, Huimin; Hoffmann, Hanne M; Iyer, Anita K et al. (2017) Chromatin status and transcription factor binding to gonadotropin promoters in gonadotrope cell lines. Reprod Biol Endocrinol 15:86
Schoeller, Erica L; Clark, Daniel D; Dey, Sandeepa et al. (2016) Bmal1 Is Required for Normal Reproductive Behaviors in Male Mice. Endocrinology 157:4914-4929
Hoffmann, Hanne M; Trang, Crystal; Gong, Ping et al. (2016) Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility. J Neurosci 36:3506-18
Hoffmann, Hanne M; Mellon, Pamela L (2016) A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance. Neurosci Commun (Houst) 2:
Skowronska-Krawczyk, Dorota; Zhao, Ling; Zhu, Jie et al. (2015) P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Mol Cell 59:931-40
Xie, Huimin; Hoffmann, Hanne M; Meadows, Jason D et al. (2015) Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development. Mol Endocrinol 29:842-55
Kauffman, Alexander S; Thackray, Varykina G; Ryan, Genevieve E et al. (2015) A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice. Biol Reprod 93:69

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