Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis
- *OncoDevelopmental Biology Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037; and ‡Departments of Obstetrics and Gynecology and Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73165
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Edited by Bert W. O'Malley, Baylor College of Medicine, Houston, TX (received for review March 11, 2003)
Abstract
Two isomers of retinoic acid (RA) may be necessary as ligands for retinoid signaling: all-trans-RA for RA receptors (RARs) and 9-cis-RA for retinoid X receptors (RXRs). This was explored by using retinaldehyde dehydrogenase (Raldh)2 -/- mouse embryos lacking mesodermal RA synthesis that display early growth arrest unless rescued by all-trans-RA administration. Because isomerization of all-trans-RA to 9-cis-RA can occur, it is unclear whether both ligands are needed for rescue. We show here that an RAR-specific ligand can rescue Raldh2 -/- embryos as efficiently as all-trans-RA, whereas an RXR-specific ligand has no effect. Further, whereas all-trans-RA was detected in embryos, 9-cis-RA was undetectable unless a supraphysiological dose of all-trans-RA was administered, revealing that 9-cis-RA is of pharmacological but not physiological significance. Because 9-cis-RA is undetectable and unnecessary for Raldh2 -/- rescue, and others have shown that 4-oxo-RA is unnecessary for mouse development, all-trans-RA emerges as the only ligand clearly necessary for retinoid receptor signaling.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: duester{at}burnham.org.
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↵ † F.A.M. and A.M. contributed equally to this work.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: RA, retinoic acid; RXR, retinoid X receptor; RAR, RA receptor; Raldh, retinaldehyde dehydrogenase; En, embryonic day n.
- Copyright © 2003, The National Academy of Sciences
