Growth Factor Regulation of the GnRH Neuron

Summary

Principal Investigator: ANDREW M WOLFE
Abstract: DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) is essential for the regulation of reproductive function. GnRH neurons sit at the top of the HPG axis and mediate the effects of a number of cues on reproduction. For example, fasting has been shown in both experimental paradigms and clinical observations to decrease reproductive function via an inhibition of GnRH release. In addition, some models ascribe a role for a permissive level of nutritional growth to trigger the onset of puberty. It is unclear how GnRH neurons respond to nutritional signals. Previous studies from our laboratory indicated that GnRH neurons respond to treatment with IGF-1 with an IGF-1 receptor dependent increase in GnRH mRNA expression that is mediated by a Ras signaling cascade. Erkl/2 activation of AP-1 activates human GnRH promoter activity and is thought to activate the mouse GnRH (mGnRH) promoter, albeit via a non-classical AP-1 element. A conditional KO mouse lacking the insulin receptor in the brain resulted in hypothalamic infertility suggesting a critical in vivo role for the insulin receptors in the brain for the regulation of reproduction. Preliminary results from transfections indicate that insulin treatment increased GnRH promoter activity in a GnRH neuronal cell line nearly 3-fold when compared to insulin's effects on a minimal GnRH promoter and that this response was blocked by a MEK inhibitor. In a fasted mouse paradigm, insulin treatment induced an activation of mouse GnRH promoter activity. These results, in total, suggest that insulin plays a regulatory role in GnRH gene expression in vitro and in vivo. I propose to identify the elements of the molecular signaling pathway for insulin and IGF-1 using classic pharmacological and binding studies. The regulation of the mGnRH promoter by insulin and IGF-1 will be mapped to identify cis-regulatory elements important for promoter responsiveness to insulin and/or IGF-1. In addition, I propose to create conditional knock out mice in which insulin receptor or IGF-1 receptor is deleted only in GnRH neurons. I will also construct a mouse in which c-Jun, one of the downstream signaling molecules for IGF-1, and perhaps insulin, signaling is deleted in GnRH neurons. These mice should prove invaluable for confirming a potential direct effect of insulin or IGF-1 receptor signaling at the level of the GnRH neuron.
Funding Period: 2003-09-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Divergent roles of growth factors in the GnRH regulation of puberty in mice
    Sara A DiVall
    Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland 21212, USA
    J Clin Invest 120:2900-9. 2010
  2. pmc Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor
    Kathryn J Brothers
    Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
    Cell Metab 12:295-305. 2010
  3. pmc Jak2 is necessary for neuroendocrine control of female reproduction
    Sheng Wu
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    J Neurosci 31:184-92. 2011
  4. pmc Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism
    Daniel Diaczok
    Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
    Mol Endocrinol 25:833-46. 2011
  5. pmc Reproductive tissues maintain insulin sensitivity in diet-induced obesity
    Sheng Wu
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Diabetes 61:114-23. 2012
  6. pmc Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin
    Sara A DiVall
    Division of Endocrinology, Department of Pediatrics, Johns Hopkins University, 600 N Wolfe Street, Park 211, Baltimore, MD 21287, United States
    Mol Cell Endocrinol 270:64-72. 2007
  7. pmc Temporal and spatial regulation of CRE recombinase expression in gonadotrophin-releasing hormone neurones in the mouse
    A Wolfe
    Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
    J Neuroendocrinol 20:909-16. 2008
  8. pmc Impaired estrogen feedback and infertility in female mice with pituitary-specific deletion of estrogen receptor alpha (ESR1)
    Surya P Singh
    Divisions of Pediatric Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    Biol Reprod 81:488-96. 2009

Scientific Experts

  • Sara A DiVall
  • Sheng Wu
  • A Wolfe
  • Fredric E Wondisford
  • Sally Radovick
  • Daniel Diaczok
  • Kathryn J Brothers
  • Surya P Singh
  • Isao Matsuo
  • C Ronald Kahn
  • Ryan S Miller
  • Marcus R Messmer
  • Yewade Ng
  • Colleen Buggs
  • Jon E Levine

Detail Information

Publications8

  1. pmc Divergent roles of growth factors in the GnRH regulation of puberty in mice
    Sara A DiVall
    Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland 21212, USA
    J Clin Invest 120:2900-9. 2010
    ..These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states...
  2. pmc Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor
    Kathryn J Brothers
    Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
    Cell Metab 12:295-305. 2010
    ....
  3. pmc Jak2 is necessary for neuroendocrine control of female reproduction
    Sheng Wu
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    J Neurosci 31:184-92. 2011
    ..These results demonstrate an essential role for Jak2 signaling in GnRH neurons for normal reproductive development and fertility in female mice...
  4. pmc Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism
    Daniel Diaczok
    Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
    Mol Endocrinol 25:833-46. 2011
    ..Taken together, these data provide in vivo evidence that Otx2 is critical for GnRH expression and reproductive competence...
  5. pmc Reproductive tissues maintain insulin sensitivity in diet-induced obesity
    Sheng Wu
    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Diabetes 61:114-23. 2012
    ..Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS...
  6. pmc Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin
    Sara A DiVall
    Division of Endocrinology, Department of Pediatrics, Johns Hopkins University, 600 N Wolfe Street, Park 211, Baltimore, MD 21287, United States
    Mol Cell Endocrinol 270:64-72. 2007
    ..Thus, Egr-1 binds the GnRH promoter at a site between -67 and -76bp from the transcriptional start site to mediate the insulin-induced increase in GnRH gene transcription...
  7. pmc Temporal and spatial regulation of CRE recombinase expression in gonadotrophin-releasing hormone neurones in the mouse
    A Wolfe
    Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
    J Neuroendocrinol 20:909-16. 2008
    ..The GnRH-CRETeR mouse can be used to study genes that may have distinct roles in reproductive physiology during the various developmental stages...
  8. pmc Impaired estrogen feedback and infertility in female mice with pituitary-specific deletion of estrogen receptor alpha (ESR1)
    Surya P Singh
    Divisions of Pediatric Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
    Biol Reprod 81:488-96. 2009
    ....