A Novel Short-Chain Alcohol Dehydrogenase from Rats with Retinol Dehydrogenase Activity, Cyclically Expressed in Uterine Epithelium1

Abstract

Retinoic acid is necessary for the maintenance of many lining epithelia of the body, such as the epithelium of the luminal surface of the uterus. Administration of estrogen to prepubertal rats induces in these epithelial cells the ability to synthesize retinoic acid from retinol, coincident with the appearance of cellular retinoic acid-binding protein, type two, which is normally present in these cells only at estrus in the mature, cycling animal. Here, we report the isolation, from a cDNA library prepared from uterine mRNA collected at the estrous stage and from a rat mammary adenocarcinoma cell line, of a cDNA that encodes a novel retinol dehydrogenase. A member of the short-chain alcohol dehydrogenase family, the encoded enzyme was capable of metabolizing retinol to retinal when expressed in cells after transfection of its cDNA. When cotransfected with the cDNA of human aldehyde 6, a known retinaldehyde dehydrogenase, the transfected cells synthesized retinoic acid from retinol. Immunohistochemical analysis revealed that the protein was present in the uterine lining epithelium of the mature animal only at estrus, coincident with the presence of cellular retinol-binding protein and cellular retinoic acid-binding protein, type two. Consequently, this novel short-chain alcohol dehydrogenase is an excellent candidate for the retinol dehydrogenase that catalyzes the first step in retinoic acid biosynthesis that occurs in uterine epithelial cells.

Multiple Retinol and Retinal Dehydrogenases Catalyze All-trans-retinoic Acid Biosynthesis in Astrocytes

“…Because Dhrs9 had been reported as a retinol dehydrogenase, we were surprised to observe that its knockdown in astrocytes resulted in increased atRA production (28,67,68). We excluded the most obvious possibility that Dhrs9 functioned as a reductase, and instead noted that Dhrs9 knockdown causes an increase in Raldh1 expression.…”

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

“…Uterine CYP26A1 activity is important for blastocyst implantation in pregnant mice (32); however, Cyp26a1 expression was low in the Müllerian duct, suggesting that RA was not catabolized in the Müllerian duct. Expression of Dhrs9, Aldh1a1, and Cyp26b1 was confirmed in the adult uterus and/or vagina, and it was regulated during the estrous cycle or by E2 treatment (20)(21)(22). Thus, these enzymes might act in the adult uterus and/or vagina.…”

“…Degradation of RA is promoted by cytochrome P450 26A1 (CYP26A1), CYP26B1, and CYP26C1 (17)(18)(19). In adult mice, Dhrs9, Aldh1a1, Cyp26, and Aldh1a2 are expressed in the uterus (20)(21)(22), whereas Aldh1a1, Aldh1a2, and Cyp26 are not detected in the vagina (20). These data suggest that RA signaling may act in the adult uterus.…”

Immunolocalization of retinoic acid biosynthesis systems in selected sites in rat

“…Retinol dehydrogenases (Roldhs) convert retinol to retinal, while retinal dehydrogenases (Raldhs) convert retinal to RA. There are four known rat Roldhs of the short chain dehydrogenase reductase family (SDR): Roldh 1, 2, and 3, and eRoldh [9][10][11][12][13]. Two human Roldh family members, hRDH4 (aka hRODH-E) and hRDH-TBE (aka hRODH-E2), have been identified [14 -20].…”

“…The uterus is sensitive to vitamin A deficiency [1,2]. The RA synthesis system in the rat uterus consists of Crbp, eRoldh, Aldh1a2, and Crabp2 [12,25,28,29]. This RA synthesis system is regulated by estrogen, and during estrus, Crbp, eRoldh, and Crabp2 are localized to the uterine epithelium, while Aldh1a2 is present within the uterine stromal cells, particularly those cells directly adjacent to the epithelium [28,30].…”