Session: S05-Initiating Steroidogenesis: Novel Mechanistic Insights
Room 121 (Moscone Center)
SF-1 (NR5A1) is a key regulator of steroidogenesis. This nuclear receptor is bound by phospholipid ligands and is modified by sumoylation. To directly assess if this post-translation modification is essential for proper SF-1 function, knock-in mice harboring an unsumoylatable form of SF-1 (Sf-1K119R,K194R, Sf-12KR) were generated. Mutant mice exhibited distinct endocrine abnormalities that reflected an inappropriate activation of hedgehog signaling and other novel SF-1 downstream targets. Defects included amplification of steroidogenic cell types, and a premature depletion of adrenal stem cells. These in vivo analyses provide definitive evidence that unmodified and sumoylated SF-1 forms function differently, with both presumably needed to regulate the full spectrum of SF-1 dosage-sensitive targets. Our findings illustrate how sumoylation is leveraged during development to achieve cell specific gene expression in multi-cellular organisms. Recent data reflecting our efforts to pharmacologically target SF-1 sumoylation will also be presented.
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