RXR FUNCTION REQUIRES BINDING TO AN ENDOGENOUS TERPENOID LIGAND

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 338-365-Metabolic & Stress Receptors in Energy Homeostasis
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-364
Grace Jones*1, Davy Jones2, Peter Teal3, Vincent Henrich4, Agnes Sapa5, Anna Krzywonos5 and Mietek Wozniak5
1Univ of Kentucky, Lexington, KY, 2University of Kentucky, Lexington, KY, 3USDA/ARS, Gainesville, FL, 4University of NC, Greensboro, NC, 5Wroclaw Medical University, Wroclaw, Poland
The issue of whether the nuclear receptor RXR must bind to an endogenous, nanomolar affinity ligand in order to perform its natural function is still unsettled (1).  On the basis of our previous studies establishing that the Drosophila melanogaster ortholog of the retinoid X receptor (“ultraspiracle,” USP) has nanomolar affinity for methyl farnesoate (2), residues in the USP ligand binding pocket were mutated to reduce binding affinity for methyl farnesoate.  Transgenic wild type USP, or the mutant USP, were expressed in a null USP background, under the control of the natural USP promoter.  The early larval lethality of the null USP background was rescued through metamorphic transition to the pupal and adult form by the transgenic wild type USP.  However, USP with a debilitated ligand binding pocket was unable to sustain proper morphogenetic development through the larval to pupal transition. This in vivo functional assay of RXR (USP) ligand binding function appears appropriate for evaluation of USP-mediated hormonal networks in some medically important vectors of disease, as a transgenic mosquito (Aedes aegypti) USP, driven by the above promoter, was also able to rescue larval Drosophila development to the adult form.

From the hormone direction, RNAi-mediated disruption of proper ring gland biosynthesis of methyl farnesoate also disrupted the same morphogenetic transition point.  We also determined that a related model dipteran (Musca domestica), treatment with a metabolically stabilized methyl farnesoate derivative (3) also disrupted this morphogenetic transition.  

These data indicate that the morphogenetic progression from the immature to the mature form in these model systems requires the involvement of a distinct endocrine axis of USP binding, in a developmentally controlled manner, to an endogenous terpenoid ligand.  This hormone/receptor axis is distinct from, but intersects with, insect hormone axes of the classical steroid (ecdysone) and methyl epoxy sesquiterpenoid (juvenile hormone)

(1) G. Wolf G. Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr. Rev.  64 (2006) 532-8. (2) G. Jones, D. Jones, P. Teal, A. Sapa, M. Wozniak, The retinoid-X receptor 788 ortholog, ultraspiracle, binds with nanomolar affinity to an endogenous morphogenetic ligand, FEBS J. 273 (2006) 4983–4996. (3) M. Romanuk , K. Sláma , F. Sorm. Constitution of a compound with a pronounced juvenile hormone activity. Proc. Natl. Acad. Sci. U. S. A. 57 (1967) 349–352.

Nothing to Disclose: GJ, DJ, PT, VH, AS, AK, MW

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

Sources of Research Support: This research was supported in part by the National Science 665 Foundation (1052142) and the National Institutes of Health 666 (GM075248-04).