Kansas City, Mo. (May 1, 2007) – Lisa Sandell, Ph.D., Senior Research Associate in the Trainor Lab, and Paul Trainor, Ph.D., Assistant Investigator, are the first and last authors, respectively, on a paper identifying a gene that plays a critical role in the metabolism of Vitamin A during embryogenesis. Vitamin A is essential for normal eye, lip/palate, limb, and organ development.

     The paper, “RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development,” was published in the May 1 issue of Genes and Development.

     Regulation of patterning and morphogenesis during embryonic development depends on tissue-specific signaling by the active form of Vitamin A, called retinoic acid. The conversion of the inactive form of Vitamin A into the active retinoic acid form requires two reactions. Whereas the second step in this process – the conversion of retinal to retinoic acid – is known to be performed by retinaldehyde dehydrogenases, the enzyme or enzymes that catalyze the first step – the oxidation of Vitamin A into retinal in the embryo – have remained unclear.

     “In an ENU-induced forward genetic screen we discovered a new mid-gestation lethal mouse mutant, called trex, which displays craniofacial, limb, and organ abnormalities,” said Dr. Sandell. “The phenotypes of trex mutant embryos are caused by a mutation in the gene encoding the short chain dehydrogenase/reductase, RDH10. Using protein modeling, enzymatic assays, and analysis of mutant embryos, we determined that RDH10^trex mutant protein lacks the ability to oxidize Vitamin A to retinal, resulting in insufficient retinoic acid signaling.”

     These findings indicate that the first oxidative step of Vitamin A metabolism is catalyzed in large part by the retinol dehydrogenase RDH10. Thus, the RDH10 enzyme is critical for the spatiotemporal synthesis of retinoic acid, and the enzymatic reaction it performs represents the identification of a new nodal point in retinoic acid metabolism during embryogenesis.

     “Vitamin A is essential for both embryonic and adult health,” said Dr. Trainor. “Too much or too little retinoic acid — caused by factors ranging from dietary deficiencies to acne drugs — can cause developmental defects. This work identifies the enzyme RDH10 as a key regulator of Vitamin A metabolism and demonstrates that genetic mutations in this gene may be responsible for congenital birth defects such as orofacial clefting and limb anomalies.”

     Additional contributing authors from the Stowers Institute include Brian Sanderson, Lab Manager II in Molecular Biology; Teri Johnson, Managing Director of Histology; Arcady Mushegian, Ph.D., Director of the Bioinformatics Center; Kendra Young, Research Technician II in Molecular Biology; Jean-Philippe Rey, Ph.D., Research Specialist I in Histology; and Karen Staehling-Hampton, Ph.D., Managing Director of Molecular Biology.

     Gennadiy Moiseyev, M.S., Ph.D., and Jian-xing Ma, M.D., Ph.D., from University of Oklahoma Health Sciences Center also contributed to the paper.

     Dr. Trainor and Dr. Mushegian hold academic appointments at the University of Kansas School of Medicine.

About the Stowers Institute
     Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.