Retinoic Acid and Alcohol/Retinol Dehydrogenase in the Mouse Adrenal Gland: A Potential Endocrine Source of Retinoic Acid during Development*

Haselbeck, Robert J.; Ang, Hwee Luan; Deltour, Louise; Duester, Gregg

doi:10.1210/endo.138.7.5274

Cited by 23 publications

(15 citation statements)

References 24 publications

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“…Our findings suggest that RA is the somatically generated meiosis-inducing substance. RA is known to be present in many embryonic tissues, including adrenal gland (39,40), mesonephros (41), and lung (42). Thus, our proposal that RA is the meiosis-inducing substance readily accounts for the ability of embryonic germ cells to initiate meiosis in diverse extragonadal sites.…”

Section: Discussionmentioning

confidence: 66%

“…Although the gonads themselves could synthesize RA, at least two possible extragonadal sources merit consideration. First, the embryonic adrenal gland, located just anterior to the gonad, is a site of robust RA synthesis during embryogenesis (39,40). Could diffusion of RA from the embryonic adrenal gland account for the anterior-to-posterior wave of Stra8 expression observed in the developing ovary (2)?…”

Section: Discussionmentioning

confidence: 99%

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Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Koubova

Menke

Zhou³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

844

976

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In mammals, meiosis is initiated at different time points in males and females, but the mechanism underlying this difference is unknown. Female germ cells begin meiosis during embryogenesis. In males, embryonic germ cells undergo G 0 ͞G 1 mitotic cell cycle arrest, and meiosis begins after birth. In mice, the Stimulated by Retinoic Acid Gene 8 (Stra8) has been found to be required for the transition into meiosis in both female and male germ cells. Stra8 is expressed in embryonic ovaries just before meiotic initiation, whereas its expression in testes is first detected after birth. Here we examine the mechanism underlying the sex-specific timing of Stra8 expression and meiotic initiation in mice. Our work shows that signaling by retinoic acid (RA), an active derivative of vitamin A, is required for Stra8 expression and thereby meiotic initiation in embryonic ovaries. We also discovered that RA is sufficient to induce Stra8 expression in embryonic testes and in vitamin Adeficient adult testes in vivo. Finally, our results show that cytochrome p450 (CYP)-mediated RA metabolism prevents premature Stra8 expression in embryonic testes. Treatment with an inhibitor specific to RA-metabolizing enzymes indicates that a cytochrome p450 from the 26 family (CYP26) is responsible for delaying Stra8 expression in embryonic testes. Sex-specific regulation of RA signaling thus plays an essential role in meiotic initiation in embryonic ovaries and precludes its occurrence in embryonic testes. Because RA signaling regulates Stra8 expression in both embryonic ovaries and adult testes, this portion of the meiotic initiation pathway may be identical in both sexes.sex determination

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Koubova

Menke

Zhou³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

844

976

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“…These findings indicate that ADH3 contributes significantly to RA generation in vivo, and under these conditions makes a larger contribution than ADH4 perhaps because of its ubiquitous expression compared with the much more limited expression pattern of ADH4. ADH4 is not expressed in liver or intestine and instead is limited to epithelia of the stomach, esophagus, skin, adrenal, and reproductive tract (31,(39)(40)(41). The observed major role of ADH1 in metabolism of a dose of retinol to RA is consistent with its expression at very high levels in liver, intestine, and several other organs (31).…”

Section: ϫ/ϫmentioning

confidence: 60%

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

Molotkov

Fan

Deltour

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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129

123

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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.

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“…5-E9.5 (18, 19) and later embryonic stages (20). Also, retinoic acid and Adh1 plus Adh4 expression have been colocalized in the adult and embryonic adrenal gland, which may function as an endocrine source of retinoic acid (21,22). We have now generated mice carrying targeted null mutations in Adh1, Adh3, and Adh4.…”

mentioning

confidence: 99%

“…Additional evidence linking both Adh1 and Adh4 to retinoic acid synthesis consists of gene expression data where these enzymes show localization in numerous adult retinoidresponsive epithelia including the epidermis (15), male reproductive tract (16), and gastrointestinal tract (17) as well as in retinoid target tissues of embryos at stages E8.5-E9.5 (18,19) and later embryonic stages (20). Also, retinoic acid and Adh1 plus Adh4 expression have been colocalized in the adult and embryonic adrenal gland, which may function as an endocrine source of retinoic acid (21,22). We have now generated mice carrying targeted null mutations in Adh1, Adh3, and Adh4.…”

mentioning

confidence: 99%

Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

Deltour

Foglio

Duester

1999

Journal of Biological Chemistry

Self Cite

166

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Targeting of mouse alcohol dehydrogenase genes Adh1, Adh3, and Adh4 resulted in null mutant mice that all developed and reproduced apparently normally but differed markedly in clearance of ethanol and formaldehyde plus metabolism of retinol to the signaling molecule retinoic acid. Following administration of an intoxicating dose of ethanol, Adh1 ؊/؊ mice, and to a lesser extent Adh4 ؊/؊ mice, but not Adh3 ؊/؊ mice, displayed significant reductions in blood ethanol clearance. Ethanol-induced sleep was significantly longer only in Adh1 ؊/؊ mice. The incidence of embryonic resorption following ethanol administration was increased 3-fold in Adh1 ؊/؊ mice and 1.5-fold in Adh4 ؊/؊ mice but was unchanged in Adh3 ؊/؊ mice. Formaldehyde toxicity studies revealed that only Adh3 ؊/؊ mice had a significantly reduced LD 50 value. Retinoic acid production following retinol administration was reduced 4.8-fold in Adh1 ؊/؊ mice and 8.5-fold in Adh4 ؊/؊ mice. Thus, Adh1 and Adh4 demonstrate overlapping functions in ethanol and retinol metabolism in vivo, whereas Adh3 plays no role with these substrates but instead functions in formaldehyde metabolism. Redundant roles for Adh1 and Adh4 in retinoic acid production may explain the apparent normal development of mutant mice. The alcohol dehydrogenase (ADH)1 family consists of numerous enzymes able to catalyze the reversible oxidation of a wide variety of xenobiotic and endogenous alcohols to the corresponding aldehydes (1). Several distinct classes of vertebrate ADH have been described, all of which are cytosolic and zincdependent but differ in substrate specificities and gene expression patterns (2, 3). Three forms that are highly conserved in mammals and other vertebrates are class I ADH (ADH1), class III ADH (ADH3), and class IV ADH (ADH4); see Ref. 1 for ADH nomenclature. Biochemical studies indicate that these three ADHs are able to utilize a wide variety of alcohol and aldehyde substrates in vitro ranging from ethanol to formaldehyde to retinol. However, the precise functions of these enzymes are not yet well established. In humans, ADH4 demonstrates higher retinol dehydrogenase activity than ADH1 with ADH1 having higher ethanol dehydrogenase activity than ADH4 and ADH3 having insignificant retinol or ethanol dehydrogenase activity (4 -6). Instead, ADH3 has glutathione-dependent formaldehyde dehydrogenase activity, i.e. upon reaction of formaldehyde with glutathione to produce S-hydroxymethylglutathione, ADH3 oxidizes the hydroxymethyl group to a formyl group to produce S-formylglutathione, which is then the substrate for a hydrolase that regenerates glutathione and produces formate (7).The potential role of ADH1 and ADH4 in retinol metabolism is particularly interesting because this pathway produces retinoic acid, which is a physiological ligand controlling numerous retinoic acid receptor signaling pathways (8). Also, the potential dual roles of ADH1 and ADH4 as ethanol and retinol dehydrogenases have led us to propose that alcohol abuse may lead to ethanol inhibition of ADH-c...

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Retinoic Acid and Alcohol/Retinol Dehydrogenase in the Mouse Adrenal Gland: A Potential Endocrine Source of Retinoic Acid during Development*

Cited by 23 publications

References 24 publications

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

Retinoic acid regulates sex-specific timing of meiotic initiation in mice

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

Metabolic Deficiencies in Alcohol Dehydrogenase Adh1,Adh3, and Adh4 Null Mutant Mice

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