The secretion of Gonadotropin-releasing hormone (GnRH, also called LHRH) is critical for regulating the pituitary-gonadal axis and ensuring reproductive competence for virtually all vertebrates. GnRH neurons migrate from the olfactory placode across the cribriform plate and olfactory bulb, into the forebrain and hypothalamus during embryonic and early postnatal development. The migratory pathway for these neurons consists of axons that originate in the vomeronasal organ (VNO), and project beyond the olfactory bulb directly into the rostral forebrain. Preliminary studies show that SDF-1/CXCR4 signaling plays a critical role in GnRH neuron migration. Virtually no GnRH neurons reach the ventral forbrain in CXCR4-/- mice. These mice may represent an ideal model for Kallmann Syndrome (KS) or Idiopathic Hypogonadotropic Hypogonadism (IHH). We will analyze the role of SDF-1/CXCR4 in vivo and in vitro studies in mouse and will seek to determine whether individuals with KS or IHH may have SDF-1 or CXCR4 gene mutations. We will also analyze the role of kisspeptin/GPR54 signaling for their ability to influence the mobility and direction of movement of subsets of GnRH neurons. These experiments are proposed to balance studies in vivo using normal and mutant mice with studies in vitro that test particular pathways or mechanisms. The complementary approach is important for ensuring that our results will be relevant to the basic biology of the GnRH neuronal system. In vivo, we will use several lines of mutant mice to analyze their roles in migration of GnRH neurons. In vitro, we will test whether different cues signal through the same or similar mechanisms to drive GnRH neuron movement/migration. We will test mechanisms in individual GnRH neurons by video microscopy using in vitro slice cultures derived from transgenic animals in which green fluorescent protein (GFP) is selectively expressed in GnRH neurons. These studies will lead to an understanding of the complex factors that guide GnRH neurons to their proper destinations in the hypothalamus to control the hypothalamic-pituitary-gonadal axis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009034-03
Application #
7618415
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Davis, Barry
Project Start
2007-07-09
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$306,491
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Knoll, John Gabriel; Clay, Colin M; Bouma, Gerrit J et al. (2013) Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain. Front Endocrinol (Lausanne) 4:140
Schwarting, Gerald A; Henion, Timothy R (2011) Regulation and function of axon guidance and adhesion molecules during olfactory map formation. J Cell Biochem 112:2663-71
Pierce, Angela; Xu, Mei; Bliesner, Brian et al. (2011) Hypothalamic but not pituitary or ovarian defects underlie the reproductive abnormalities in Axl/Tyro3 null mice. Mol Cell Endocrinol 339:151-8
Henion, Timothy R; Faden, Ashley A; Knott, Thomas K et al. (2011) ?3GnT2 maintains adenylyl cyclase-3 signaling and axon guidance molecule expression in the olfactory epithelium. J Neurosci 31:6576-86
Wierman, Margaret E; Kiseljak-Vassiliades, Katja; Tobet, Stuart (2011) Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol 32:43-52
Pierce, Angela; Bliesner, Brian; Xu, Mei et al. (2008) Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol 22:2481-95
Gill, John C; Wadas, Brandon; Chen, Peilin et al. (2008) The gonadotropin-releasing hormone (GnRH) neuronal population is normal in size and distribution in GnRH-deficient and GnRH receptor-mutant hypogonadal mice. Endocrinology 149:4596-604
Schwarting, Gerald A; Wierman, Margaret E; Tobet, Stuart A (2007) Gonadotropin-releasing hormone neuronal migration. Semin Reprod Med 25:305-12