The secretion of gonadotropin-releasing hormone (GnRH) 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 majority of GnRH neurons migrate along the VNN through the nasal cavity. GnRH neurons then leave the main VNN and follow a small group of axons directly into the brain. We have recently identified the migratory track as a subset of the vomeronasal nerve. Preliminary studies suggest that 3 events play a role in the regulation of GnRH migration: i) GnRH neurons interact specifically with ligands on the migratory pathway; and ii) a group of co-migrating GABAergic neurons modulates the migration of GnRH neurons , and iii) selective axon branching and guidance of the caudal VNN establishes a chemically unique track for GnRH neurons. Our objective is to determine the molecular basis of directed GnRH neuron migration. Perturbation studies with enzymes, peptides, ligands, proteins and antibodies using in vitro slice cultures of the nose and forebrain, and in vivo will define the factors that regulate movement along the known route of GnRH cell migration. We will develop an in vivo marker for GnRH neurons in transgenic mice using transgenes containing the human GnRH promoter fused to green fluorescent protein cDNA. Green fluorescent protein (GFP)containing transgenic GnRH cells fluoresce when exposed to 395- 470nm light, and are thus identifiable microscopically in living tissue. GFP transgenic mice, in conjunction with slice cultures will allow us to test hypotheses that GnRH neurons use caudal branches of the VNN as guides for migration into the forebrain. The developmental relationship of the olfactory system and the forebrain is clinically significant. X-linked Kallmann syndrome is caused by a defect in the development of the olfactory system. This syndrome is characterized primarily by the inability to smell, anosmia; and abnormal development of the gonads, hypogonadotrophic hypogonadism. it has also been associated with numerous other neurological problems, including mental retardation. Results from these studies will aid our understanding of the development of the nervous system.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033441-02
Application #
2634956
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1997-01-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Eunice Kennedy Shriver Center Mtl Retardatn
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02254
Schwarting, Gerald A; Wierman, Margaret E; Tobet, Stuart A (2007) Gonadotropin-releasing hormone neuronal migration. Semin Reprod Med 25:305-12
Schwarting, Gerald A; Henion, Timothy R; Nugent, J David et al. (2006) Stromal cell-derived factor-1 (chemokine C-X-C motif ligand 12) and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain. J Neurosci 26:6834-40
Tobet, Stuart A; Schwarting, Gerald A (2006) Minireview: recent progress in gonadotropin-releasing hormone neuronal migration. Endocrinology 147:1159-65
Bless, Elizabeth; Raitcheva, Denitza; Henion, Timothy R et al. (2006) Lactosamine modulates the rate of migration of GnRH neurons during mouse development. Eur J Neurosci 24:654-60
Vendel, Andrew C; Terry, Mark D; Striegel, Amelia R et al. (2006) Alternative splicing of the voltage-gated Ca2+ channel beta4 subunit creates a uniquely folded N-terminal protein binding domain with cell-specific expression in the cerebellar cortex. J Neurosci 26:2635-44
Bless, Elizabeth P; Walker, Heather J; Yu, Kwok W et al. (2005) Live view of gonadotropin-releasing hormone containing neuron migration. Endocrinology 146:463-8
Schwarting, Gerald A; Raitcheva, Denitza; Bless, Elizabeth P et al. (2004) Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons. Eur J Neurosci 19:11-20
Heger, Sabine; Seney, Marianne; Bless, Elizabeth et al. (2003) Overexpression of glutamic acid decarboxylase-67 (GAD-67) in gonadotropin-releasing hormone neurons disrupts migratory fate and female reproductive function in mice. Endocrinology 144:2566-79
Leupen, Sarah M; Tobet, Stuart A; Crowley Jr, W F et al. (2003) Heterogeneous expression of the potassium-chloride cotransporter KCC2 in gonadotropin-releasing hormone neurons of the adult mouse. Endocrinology 144:3031-6
Reed, Karen L; MacIntyre, Janet K; Tobet, Stuart A et al. (2002) The spatial relationship of gamma-aminobutyric acid (GABA) neurons and gonadotropin-releasing hormone (GnRH) neurons in larval and adult sea lamprey, Petromyzon marinus. Brain Behav Evol 60:1-12

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