Gonadotropin-releasing hormone (GnRH) neurons are central to the initiation and maintenance of reproductive function in diverse vertebrates. During development, GnRH neurons enter sequential stages to mature into a functional network capable of supporting reproduction in adulthood. These stages include cell fate specification in the olfactory placodes, migration into the forebrain, and targeting of axons to the median eminence for hormone release. Signals that trigger GnRH neuronal entrance into these stages, as well as factors that regulate maturation within each stage remain largely unknown. We hypothesize that neurotrophic factors provide time-specific signals to drive the progression of GnRH neurons development. In this proposal, we will use a candidate neurotrophic factor approach and focus on the actions of a family of growth factors shown to have profound neurotrophic activities in cultured primary and immortalized GnRH neurons: the fibroblast growth factors (FGFs). Further, the actions of insulin-like growth factor I (IGF-I), a neurotrophic factor previously shown to act independently and/or collaboratively with FGF-2, will be investigated. This proposal will utilize a combination of existing transgenic models and primary GnRH neuron cultures to address the following Aims: to determine 1) if receptors for FGFs are expressed in a time-specific manner during development, 2) if FGFs alter GnRH progenitor cell expansion and the emergence of GnRH neurons, 3) if FGFs alter the migration of GnRH neurons into the forebrain, 4) if FGFs promote GnRH axon targeting, and 5) if IGF-I acts independently or synergistically with FGFs to promote the survival of GnRH neurons. Together, results from these Aims will provide important clues regarding how a neuroendocrine system critical for vertebrate reproduction develops and matures with the guidance of neurotrophic factors. Further, these results will aid in the understanding of cellular and molecular basis of developmental reproductive abnormalities that result from GnRH deficiency. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042634-04
Application #
7151469
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Lamar, Charisee A
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$187,181
Indirect Cost
Name
University of Colorado at Boulder
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Miller, Ann V; Kavanaugh, Scott I; Tsai, Pei-San (2016) Disruption of the Suprachiasmatic Nucleus in Fibroblast Growth Factor Signaling-Deficient Mice. Front Endocrinol (Lausanne) 7:11
Zhang, Wei; Johnson, Joshua I; Tsai, Pei-San (2015) Fgf8-Deficient Mice Compensate for Reduced GnRH Neuronal Population and Exhibit Normal Testicular Function. Front Endocrinol (Lausanne) 6:151
Brooks, Leah R; Pals, Heide L; Enix, Courtney L et al. (2014) Fibroblast growth factor 8 deficiency compromises the functional response of the serotonergic system to stress. PLoS One 9:e101420
Brooks, Leah R; Enix, Courtney L; Rich, Samuel C et al. (2014) Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system. Behav Brain Res 264:74-81
Miraoui, Hichem; Dwyer, Andrew A; Sykiotis, Gerasimos P et al. (2013) Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 92:725-43
Rochester, Johanna R; Chung, Wilson C J; Hayes, Tyrone B et al. (2012) Opposite-sex housing reactivates the declining GnRH system in aged transgenic male mice with FGF signaling deficiency. Am J Physiol Endocrinol Metab 303:E1428-39
Brooks, Leah R; Le, Carter Duyet V; Chung, Wilson C et al. (2012) Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons. Behav Brain Funct 8:47
Tata, Brooke K; Chung, Wilson C J; Brooks, Leah R et al. (2012) Fibroblast growth factor signaling deficiencies impact female reproduction and kisspeptin neurons in mice. Biol Reprod 86:119
McCabe, Mark J; Gaston-Massuet, Carles; Tziaferi, Vaitsa et al. (2011) Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab 96:E1709-18
Tsai, Pei-San; Brooks, Leah R; Rochester, Johanna R et al. (2011) Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus. Front Neuroendocrinol 32:95-107

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