Normal hypothalamic release of gonadotropin releasing hormone (GnRH) is central to regulation of the hypothalamic-pituitary (HP) axis and fertility in mammals including humans. Current therapeutic strategies to control fertility focus on pharmacological control of the HP axis and GnRH. Further; GnRH agonist administration is a key anti-proliferative treatment for some forms of cancer. Our studies of GnRH action define a novel network of cell signaling pathways comprised of calcium and MAPK cascades that target genes essential for the differentiated function of the gonadotrope. Compartmentalized calcium signals are essential for differential activation of MAPKs in gonadotropes. Preliminary studies reveal that specific calcium signals may mediate MAPK activation via calmodulin and the tyrosine kinase, Pyk2. Further, the GnRH receptor and c-raf kinase constitutively reside in specific low density membrane compartments, likely required for assembly of a signaling """"""""module"""""""" at the plasma membrane.
The specific aims of this proposal are:
Aim 1. Define the GnRH signaling pathway in differentiated mouse gonadotropes.
This aim seeks to define GnRH signaling mechanisms in fully differentiated gonadotropes, uniquely marked by GFP in transgenic mice. We will examine sexually dimorphic MAPK responses to GnRH and define the gene profile induced by GnRH in gonadotropes.
Aim 2 : Define the relationship between compartmentalized calcium signals and activation of the ERK and JNK pathways by GnRH. Calcium signaling is required for GnRH-induced ERK activation.
Aim 2 examines the role of calmodulin as a calcium sensor and Pyk2 as a calcium-sensitive enzyme that may couple PKC to c-rafkinase activation.
Aim 3 : Determine the extent and role of compartmentalization of signaling molecules in low-buoyant density membrane rafts in GnRH action.
Aim 3 will define the activities present in membrane rafts in gonadotropes, determine the domain requirements for c-raf kinase localization and examine protein-protein interactions that are required for the organization of a putative membrane associated GnRH signaling """"""""module"""""""".
Aim 4 : Define the role of MAPK signaling molecules in GnRH-mediated signaling in vivo.
Aim 4 defines the in vivo requirements for ERK l and ERK 2 in the regulation of a GnRH-inducible gene program following ovariectomy in mice. We have obtained three specialized mouse models that provide the unique opportunity to examine the requirement for MAPK signaling within the hvpothalamo-pituitary axis in vivo.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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De Paolo, Louis V
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Cornell University
Other Basic Sciences
Schools of Veterinary Medicine
United States
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Brown, Jessica L; Xie, Jianjun; BrieƱo-Enriquez, Miguel Angel et al. (2018) Sex- and Age-Specific Impact of ERK Loss Within the Pituitary Gonadotrope in Mice. Endocrinology 159:1264-1276
Brown, Jessica L; Roberson, Mark (2017) Novel Insights into Gonadotropin-Releasing Hormone Action in the Pituitary Gonadotrope. Semin Reprod Med 35:130-138
Navratil, Amy M; Dozier, Melissa G; Whitesell, Jennifer D et al. (2014) Role of cortactin in dynamic actin remodeling events in gonadotrope cells. Endocrinology 155:548-57
Bliss, Stuart P; Navratil, Amy M; Xie, Jianjun et al. (2012) ERK signaling, but not c-Raf, is required for gonadotropin-releasing hormone (GnRH)-induced regulation of Nur77 in pituitary gonadotropes. Endocrinology 153:700-11
Wierman, Margaret E; Xu, Mei; Pierce, A et al. (2012) Extracellular signal-regulated kinase 1 and 2 are not required for GnRH neuron development and normal female reproductive axis function in mice. Neuroendocrinology 95:289-96
Navratil, Amy M; Bliss, Stuart P; Roberson, Mark S (2010) Membrane rafts and GnRH receptor signaling. Brain Res 1364:53-61
Bliss, Stuart P; Navratil, Amy M; Xie, Jianjun et al. (2010) GnRH signaling, the gonadotrope and endocrine control of fertility. Front Neuroendocrinol 31:322-40
Bliss, Stuart P; Miller, Andrew; Navratil, Amy M et al. (2009) ERK signaling in the pituitary is required for female but not male fertility. Mol Endocrinol 23:1092-101
Xie, Jianjun; Allen, Krystal H; Marguet, Amelia et al. (2008) Analysis of the calcium-dependent regulation of proline-rich tyrosine kinase 2 by gonadotropin-releasing hormone. Mol Endocrinol 22:2322-35
Xie, Jianjun; Bliss, Stuart P; Nett, Terry M et al. (2005) Transcript profiling of immediate early genes reveals a unique role for activating transcription factor 3 in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone. Mol Endocrinol 19:2624-38

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