Short-chain retinol dehydrogenases/reductases Involvement in retinoid metabolism and expression in embryonic and adult mouse

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Retinoids are needed in the embryo to ensure proper development and in the adult forvision, maintenance of epithelia and sperm production. Retinol is oxidised within the cell generating retinal and, irreversibly, retinoic acid. In the eye, the biologically active retinoidis 11 -cis-retinal, whereas all -trans-retinoic and 9 -cis-retinoic acid are active in extra-ocular tissues. The retinoic acid receptor (RAR) and the retinoid X receptor (RXR) act as ligand-dependent transcription factors by binding to retinoic acid responsive elements (RAREs), regulating the transcription of target genes.Some microsomal members of the short-chain dehydrogenase/reductase family (SDR) are thought to be responsible for the in vivo oxidation of retinol to retinal. This work describes the cloning and characterisation of a 32 kDa membrane-bound SDR, designated RDH4.RDH4 oxidises both 9 -cis-retinol and 11 -cis-retinol in vitro, suggesting that RDH4 has a dual role in retinoid metabolism; as an 11 -cis-retinol dehydrogenase in the eye, and as a 9 -cis-retinol dehydrogenase in extra-ocular tissues.The expression pattern of RDH4 in the embryonic and adult mouse was investigated using in situ hybridisation and immunohistochemistry. RDH4 was first detected at 8.5 dpc, in the heart and in anterior mesenchyme. Later,RDH4 was detected in the myotome of the somites, in the notochord, in endothelial cells, in the retinal pigment epithelium and in thebronchi.RDH4 was expressed in the CNS;in the roof plate of the hindbrain, and in the floor plate of the hindbrain and caudal midbrain. In the adult, RDH4 was expressed in the liver, kidney, lung and epidermis. In conclusion,RDH4 was expressed during embryogenesisin several tissues known to synthesise, or to depend on, regulated amounts of retinoic acid for normal development. Another SDR,CRAD1, co-localised with RDH4 in the embryo, with the exception of the adrenal glands and cells in the rhombomeres, suggesting functional redundancy. When studying the co-localisation of RDH4 and retinal dehydrogenases, few sites of co-localisation were found, indicating that other, yet to be identified, aldehyde dehydrogenases exist in the embryo.