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RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development

¹ Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA; ² Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA; ³ Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA; ⁴ Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas School of Medicine, Kansas City, Kansas 66160, USA; ⁵ Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, Kansas 66160, USA

Regulation of patterning and morphogenesis during embryonic development depends on tissue-specific signaling by retinoic acid (RA), the active form of Vitamin A (retinol). The first enzymatic step in RA synthesis, the oxidation of retinol to retinal, is thought to be carried out by the ubiquitous or overlapping activities of redundant alcohol dehydrogenases. The second oxidation step, the conversion of retinal to RA, is performed by retinaldehyde dehydrogenases. Thus, the specific spatiotemporal distribution of retinoid synthesis is believed to be controlled exclusively at the level of the second oxidation reaction. In an N-ethyl-N-nitrosourea (ENU)-induced forward genetic screen we discovered a new midgestation lethal mouse mutant, called trex, which displays craniofacial, limb, and organ abnormalities. The trex phenotype is caused by a mutation in the short-chain dehydrogenase/reductase, RDH10. Using protein modeling, enzymatic assays, and mutant embryos, we determined that RDH10^trex mutant protein lacks the ability to oxidize retinol to retinal, resulting in insufficient RA signaling. Thus, we show that the first oxidative step of Vitamin A metabolism, which is catalyzed in large part by the retinol dehydrogenase RDH10, is critical for the spatiotemporal synthesis of RA. Furthermore, these results identify a new nodal point in RA metabolism during embryogenesis.

[Keywords: Retinoic acid; Vitamin A; orofacial cleft; limb]

Received January 19, 2007; revised version accepted March 14, 2007.

E-MAIL pat@stowers-institute.org; FAX (816) 926-2051.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1533407

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