title: The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development.
abstract: Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA-oxidizing enzymes; however, the contribution of retinaldehyde reductases to ATRA metabolism is not completely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic retinoid metabolism using a Dhrs3-deficient mouse. Lack of DHRS3 leads to a 40% increase in the levels of ATRA and a 60% and 55% decrease in the levels of retinol and retinyl esters, respectively, in Dhrs3(-/-) embryos compared to wild-type littermates. Furthermore, accumulation of excess ATRA is accompanied by a compensatory 30-50% reduction in the expression of ATRA synthetic genes and a 120% increase in the expression of the ATRA catabolic enzyme Cyp26a1 in Dhrs3(-/-) embryos vs. controls. Excess ATRA also leads to alterations (40-80%) in the expression of several developmentally important ATRA target genes. Consequently, Dhrs3(-/-) embryos die late in gestation and display defects in cardiac outflow tract formation, atrial and ventricular septation, skeletal development, and palatogenesis. These data demonstrate that the reduction of retinaldehyde by DHRS3 is critical for preventing formation of excess ATRA during embryonic development.
authors.affiliation: 1Department of Pharmacology and Toxicology, School of Pharmacy, 5060-Malott Hall, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045, USA. alexmoise@ku.edu.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Billings
authors.forename: Keely
authors.initials: K
authors.lastname: Pierzchalski
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Butler Tjaden
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Pang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moise
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005318:Fetal Heart / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D012172:Retinaldehyde / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; C586097:DHRS3 protein, mouse; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase; D012172:Retinaldehyde
keywords: development; metabolism; nuclear receptors; retinoid; vitamin A