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Kam, RK, Shi, W, Chan, SO, Chen, Y, Xu, G, Lau, CB, Fung, KP, Chan, WY and Zhao, H' (2013) dhrs3 attenuates retinoic acid signaling and is required for early embryonic patterning. J. Biol. Chem. '

All-trans retinoic acid (atRA) is an important morphogen involved in many developmental processes, including neural differentiation, body axis formation, and organogenesis. During the early embryonic development, atRA is synthesized from all-trans retinal (atRAL) in an irreversible reaction mainly catalyzed by retinal dehydrogenase 2 (aldh1a2), while atRAL is converted from all-trans retinol (atROL) via reversible oxidation by retinol dehydrogenases (RDHs), members of the short-chain dehydrogenase/reductase (SDR) family. atRA is degraded by cytochrome P450, family 26 (cyp26). We have previously identified a short-chain dehydrogenase/reductase 3 (dhrs3), which showed differential expression patterns in Xenopus embryos. We showed here that the expression of dhrs3 was induced by atRA treatment and overexpression of Xenopus nodal related 1 (xnr1) in animal cap assay. Overexpression of dhrs3 enhanced the phenotype of excessive cyp26a1. In embryos overexpressing aldh1a2 or retinol dehydrogenase 10 (rdh10) in the presence of their respective substrates, dhrs3 counteracted the action of aldh1a2 or rdh10, indicating that RA signaling is attenuated. Knockdown of dhrs3 by antisense morpholino oligonucleotides resulted in a phenotype of shortened anteroposterior axis, reduced head structure and perturbed somitogenesis, which were also found in embryos treated with an excess of atRA. Examination of the expression of brachyury, not, goosecoid and papc indicated that convergent extension movement was defective in dhrs3 morphants. Taken together, these studies suggest that dhrs3 participates in atRA metabolism through reducing atRAL levels, and is required for proper anteroposterior axis formation, neuroetoderm patterning, and somitogenesis.

PubMed Online version:10.1074/jbc.M113.514984