title: RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development.
abstract: Regulation of patterning and morphogenesis during embryonic development depends on tissue-specific signaling by retinoic acid (RA), the active form of Vitamin A (retinol). The first enzymatic step in RA synthesis, the oxidation of retinol to retinal, is thought to be carried out by the ubiquitous or overlapping activities of redundant alcohol dehydrogenases. The second oxidation step, the conversion of retinal to RA, is performed by retinaldehyde dehydrogenases. Thus, the specific spatiotemporal distribution of retinoid synthesis is believed to be controlled exclusively at the level of the second oxidation reaction. In an N-ethyl-N-nitrosourea (ENU)-induced forward genetic screen we discovered a new midgestation lethal mouse mutant, called trex, which displays craniofacial, limb, and organ abnormalities. The trex phenotype is caused by a mutation in the short-chain dehydrogenase/reductase, RDH10. Using protein modeling, enzymatic assays, and mutant embryos, we determined that RDH10(trex) mutant protein lacks the ability to oxidize retinol to retinal, resulting in insufficient RA signaling. Thus, we show that the first oxidative step of Vitamin A metabolism, which is catalyzed in large part by the retinol dehydrogenase RDH10, is critical for the spatiotemporal synthesis of RA. Furthermore, these results identify a new nodal point in RA metabolism during embryogenesis.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Sandell
authors.forename: Brian W
authors.initials: BW
authors.lastname: Sanderson
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.forename: Teri
authors.initials: T
authors.lastname: Johnson
authors.forename: Arcady
authors.initials: A
authors.lastname: Mushegian
authors.forename: Kendra
authors.initials: K
authors.lastname: Young
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rey
authors.forename: Jian-xing
authors.initials: JX
authors.lastname: Ma
authors.forename: Karen
authors.initials: K
authors.lastname: Staehling-Hampton
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics* / Q000502:physiology*; D005121:Extremities / Q000196:embryology; D005147:Facial Bones / Q000196:embryology; D005260:Female; D005804:Genes, Lethal; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D015398:Signal Transduction; D012886:Skull / Q000196:embryology; D014212:Tretinoin / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase