Impaired retinol utilization in Adh4 alcohol dehydrogenase mutant mice.
Adh4, a member of the mouse alcohol dehydrogenase (ADH) gene family, encodes an enzyme that functions in vitro as a retinol dehydrogenase in the conversion of retinol to retinoic acid, an important developmental signaling molecule. To explore the role of Adh4 in retinoid signaling in vivo, gene targeting was used to create a null mutation at the Adh4 locus. Homozygous Adh4 mutant mice were viable and fertile and demonstrated no obvious defects when maintained on a standard mouse diet. However, when subjected to vitamin A deficiency during gestation, Adh4 mutant mice demonstrated a higher number of stillbirths than did wild-type mice. The proportion of liveborn second generation vitamin A-deficient newborn mice was only 15% for Adh4 mutant mice but 49% for wild-type mice. After retinol administration to vitamin A-deficient dams in order to rescue embryonic development, Adh4 mutant mice demonstrated a higher resorption rate at stage E12.5 (69%), compared with wild-type mice (30%). The relative ability of Adh4 mutant and wild-type mice to metabolize retinol to retinoic acid was measured after administration of a 100-mg/kg dose of retinol. Whereas kidney retinoic acid levels were below the level of detection in all vehicle-treated mice (< 1 pmol/g), retinol treatment resulted in very high kidney retinoic acid levels in wild-type mice (273 pmol/g) but 8-fold lower levels in Adh4 mutant mice (32 pmol/g), indicating a defect in metabolism of retinol to retinoic acid. These findings demonstrate that another retinol dehydrogenase can compensate for a lack of Adh4 when vitamin A is sufficient, but that Adh4 helps optimize retinol utilization under conditions of both retinol deficiency and excess.
Gene Regulation Program, Burnham Institute, La Jolla, California 92037, USA.
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D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006720:Homozygote; D007527:Isoenzymes / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*; D014802:Vitamin A Deficiency
D007527:Isoenzymes; D014801:Vitamin A; D014212:Tretinoin; D000426:Alcohol Dehydrogenase