SF-1-Key Mediator of Endocrine Development and Function

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DESCRIPTION (provided by applicant): The orphan nuclear receptor steroidogenic factor 1 (SF-1) plays essential roles in endocrine development and function. SF-1 knockout (KO) mice exhibit adrenal and gonadal agenesis, impaired pituitary gonadotrope function, and marked structural abnormalities of the ventromedial hypothalamic nucleus (VMH), a hypothalamic region linked to energy homeostasis and reproductive behavior. Ongoing studies seek to expand our understanding of these pleiotropic roles of SF-1, focusing specifically on the VMH. First, we will examine the phenotype of VMH-specific SF-1 KO mice, allowing us to delineate primary roles of SF-1 within VMH neurons. We also will use a transgenic enhanced green fluorescent protein (eGFP) reporter gene directed by SF-1 regulatory sequences to follow SF-1-expressing neurons ex vivo in hypothalamic slice preparations, comparing neuronal migration and VMH development in wild-type and SF-1 KO mice. The SF-1/eGFP lineage marker also will used to purify SF-1-expressing neurons specifically from the VMH of wild-type and SF-1 KO mice (either global or VMH-specific), allowing us to compare the gene expression profiles of the same cells in the presence or absence of SF-1. Candidate target genes of SF-1 in the VMH will be examined to determine if they are direct targets of SF-1 in neuronal transfection experiments. Finally, the SF-1 sequences that targeted eGFP expression will be used to target to the VMH a number of gene products implicated in body weight regulation, allowing us to rescue expression specifically in the VMH. Molecules to be examined include the leptin receptor, the melanocortin 3 receptor (MC3-R), and tubby. These studies will provide novel insights into the ways in which SF-1 exerts its essential actions in VMH development and function.