Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3

doi:10.1073/pnas.082093299

Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3

^*Gene Regulation Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037; and ^§Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain

Communicated by Hector F. DeLuca, University of Wisconsin, Madison, WI (received for review December 17, 2001)

Abstract

Influence of vitamin A (retinol) on growth depends on its sequential oxidation to retinal and then to retinoic acid (RA), producing a ligand for RA receptors essential in development of specific tissues. Genetic studies have revealed that aldehyde dehydrogenases function as tissue-specific catalysts for oxidation of retinal to RA. However, enzymes catalyzing the first step of RA synthesis, oxidation of retinol to retinal, remain unclear because none of the present candidate enzymes have expression patterns that fully overlap with those of aldehyde dehydrogenases during development. Here, we provide genetic evidence that alcohol dehydrogenase (ADH) performs this function by demonstrating a role for Adh3, a ubiquitously expressed form. Adh3 null mutant mice exhibit reduced RA generation in vivo, growth deficiency that can be rescued by retinol supplementation, and completely penetrant postnatal lethality during vitamin A deficiency. ADH3 was also shown to have in vitro retinol oxidation activity. Unlike the second step, the first step of RA synthesis is not tissue-restricted because it is catalyzed by ADH3, a ubiquitous enzyme having an ancient origin.

Footnotes

↵ † Present address: Institut Cochin de Genetique Moleculaire, Institut National de la Santé et de la Recherche Médicale U257, 24 Rue du Faubourg Saint Jacques, 75014 Paris, France.
↵ ‡ Present address: Centre National de Génotypage, 2 Rue Gaston Crémieux, BP 191, 91006 Evry Cedex, France.
↵ ¶ To whom reprints requests should be addressed. E-mail: duester{at}burnham.org.
Abbreviations:

ADH,

alcohol dehydrogenase;

Adh1,

mouse class I ADH gene;

Adh3,

mouse class III ADH gene;

Adh4,

mouse class IV ADH gene;

RA,

retinoic acid;

RALDH2,

retinaldehyde dehydrogenase 2;

SDR,

short-chain dehydrogenase/reductase;

VAD,

vitamin A deficiency;

CRBPI,

cellular retinol-binding protein type I;

WT,

wild type