FP06-1 Sumoylation Of SF1 Regulates MICE Adrenal Development

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 381-386-Steroid Hormone Actions, Biosynthesis & Metabolism
Basic/Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-385
Yewei Xing*1, Mohamad Zubair1, Holly A Ingraham2 and Gary D Hammer1
1University of Michigan, Ann Arbor, MI, 2University of California San Francisco, San Francisco, CA
Sf1 (Nr5A1) is a critical nuclear receptor involved in adrenocortical development and homeostasis. Sf1 knockout mice are born with adrenal aplasia while Sf1 haplo-insufficient mice exhibit defects in homeostasis of the adult gland. In addition to gene dosage, post-translational modifications including reciprocal phosphorylation and SUMOylation also play important roles in regulating Sf1 function.  Specifically, our prior studies reported that SUMOylation of Sf1 inhibits CDK7-mediated phosphorylation of Sf1.  Despite the reported decreased expression of a subset of SUMO-sensitive genes in the presence of SUMOylated Sf1, the physiological role of SUMOylation of Sf1 in adrenocortical development and homeostasis remains unclear. In this study, the SUMO-deficient Sf1 knock-in mouse (Sf-1 that is unable to be SUMOylated) was crossed with the FAdE-Ad4bp-LacZ transgenic reporter line.  The Fetal Adrenal Enhancer of Sf1 activates transcription in a spatially and temporally restricted manner – only in the fetal zone of the adrenal cortex and only during embryonic life.

We found that the expression of LacZ was abnormally maintained in an abnormally retained fetal zone through P30 in the mutant male mouse. A similar retention of the fetal zone has been observed in mice and in patients with loss-of-function mutations in Dax1 (Nr0B1). This result is in contrast to the normal regression of the fetal zone at puberty in wildtype male mice. Because we have shown previously that FAdE-mediated expression of Sf1 is maintained by auto-activation of FAdE by Sf1 itself, we hypothesize that SUMOylation of Sf1 is important for full extinction of FAdE enhancer activity and ultimate regression of the fetal zone.  Further in-vitro studies using FAdE-luciferase constructs confirm that SUMO-tagged Sf1 is markedly deficient in activating FAdE activity in 293T cells compared to SUMO-deficient Sf1.  Future efforts will focus on examining the molecular mechanism by which SUMOylation of Sf1 together with Dax1 regulates FAdE activity during development.

Disclosure: GDH: Consultant, orphagen, Founder, Atterocor, Consultant, Embera, Advisory Group Member, Embera, Consultant, HRA Pharma, Consultant, Corcept, Consultant, Isis, Advisory Group Member, orphagen, Consultant, OSI-Astella. Nothing to Disclose: YX, MZ, HAI

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm