RRC ID 33653
Author Feng L, Hernandez RE, Waxman JS, Yelon D, Moens CB.
Title Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism.
Journal Dev. Biol.
Abstract Retinoic acid (RA) is an important developmental signaling molecule responsible for the patterning of multiple vertebrate tissues. RA is also a potent teratogen, causing multi-organ birth defects in humans. Endogenous RA levels must therefore be tightly controlled in the developing embryo. We used a microarray approach to identify genes that function as negative feedback regulators of retinoic acid signaling. We screened for genes expressed in early somite-stage embryos that respond oppositely to treatment with RA versus RA antagonists and validated them by RNA in situ hybridization. Focusing on genes known to be involved in RA metabolism, we determined that dhrs3a, which encodes a member of the short-chain dehydrogenase/reductase protein family, is both RA dependent and strongly RA inducible. Dhrs3a is known to catalyze the reduction of the RA precursor all-trans retinaldehyde to vitamin A; however, a developmental function has not been demonstrated. Using morpholino knockdown and mRNA over-expression, we demonstrate that Dhrs3a is required to limit RA levels in the embryo, primarily within the central nervous system. Dhrs3a is thus an RA-induced feedback inhibitor of RA biosynthesis. We conclude that retinaldehyde availability is an important level at which RA biosynthesis is regulated in vertebrate embryos.
Volume 338(1)
Pages 1-14
Published 2010-2-1
DOI 10.1016/j.ydbio.2009.10.029
PII S0012-1606(09)01288-3
PMID 19874812
PMC PMC2858591
MeSH Alcohol Oxidoreductases / genetics Alcohol Oxidoreductases / metabolism* Animals Body Patterning / drug effects Embryo, Nonmammalian / cytology Embryo, Nonmammalian / drug effects Embryo, Nonmammalian / enzymology Feedback, Physiological* / drug effects Gene Expression Regulation, Developmental / drug effects Gene Knockdown Techniques Nervous System / drug effects Nervous System / enzymology Neurons / cytology Neurons / drug effects Neurons / enzymology Oligonucleotide Array Sequence Analysis RNA / genetics Reproducibility of Results Retinal Dehydrogenase / genetics Retinal Dehydrogenase / metabolism Signal Transduction / drug effects Tretinoin / metabolism* Tretinoin / pharmacology Zebrafish Proteins / genetics Zebrafish Proteins / metabolism*
IF 3.262
Times Cited 52
Zebrafish giraffe/rw716