Gonadotropin releasing hormone (GnRH) is synthesized and released by neurons in the hypothalamus and is the primary neural signal regulating reproduction in mammals. Reproductive function is inhibited by food restriction and the signals that permit function during the fed state are thought to be integrated at the level of the hypothalamus. The early growth response-1 (Egr-1) gene and insulin have been shown to be independently necessary for reproduction at the central nervous system level in knockout mice models. The long-term objective of this proposal is to characterize a role for Egr-1 and insulin in reproduction by defining their role in the GnRH neuron using a GnRH immortalized cell line.
Specific aim 1 strives to characterize the pathways involved in insulin signaling in the GnRH neuron with Egr-1 as a mediator and the GnRH gene as a target gene. Functional studies with pathway inhibitors and RNA interference are proposed.
Specific aim 2 will investigate the interactions between the transcription factor Egr-1 and the GnRH gene. Protein-DNA binding studies will be performed on candidate regions of the GnRH promoter. This could define a link between nutritional status and reproductive competency at a molecular level. ? ?
| DiVall, Sara A; Radovick, Sally; Wolfe, Andrew (2007) Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin. Mol Cell Endocrinol 270:64-72 |
