The primary goal of our research is to identify molecular pathways controlling development of the urogenital tract.

Dietary vitamin A is essential for morphogenesis of the urogenital tract. The vitamin A signal is transduced by retinoids, active vitamin A metabolites that bind to and activate proteins belonging to a family of nuclear receptors (retinoic acid receptors and retinoid-X-receptors). To elucidate molecular pathways important for development of the urogenital tract, we have generated mouse mutants with impaired vitamin A signaling, either by deleting retinoid receptors, or by deleting retinoid-synthesizing enzymes. These animals display renal hypoplasia and mega-ureter similar to malformations seen in fetal vitamin A deficiency. Our initial studies revealed that vitamin A was required for maintaining expression of the receptor tyrosine kinase ret in embryonic kidneys. Since ret is required for outgrowth of the ureteric bud and branching within the embryonic kidney, these findings suggested that abnormalities in retinoid-mutants might result from down-regulation of ret in the embryonic kdiney. To directly address this question, we tested whether forced expression of ret could rescue renal malformations in mutants with impaired vitamin A signaling. These studies clearly demonstrated that vitamin A controls branching morphogenesis via ret expression. In the embryonic kidney, retinoids and retinoid receptors are co-localized in stromal mesenchyme, while ret is expressed in the ureteric bud epithelium. Thus, retinoid regulation of ret is likely to be indirect, mediated by secreted stromal cell signals that act on epithelial cells inducing ret expression. Our future goals are aimed at elucidating these signaling molecules controlling ret expression. Mutations or rearrangements in the ret gene result in Hirschsprung’s disease, cancer and renal malformations, and identification of vitamin A as a regulator of ret expression is an important step in understanding the etiology of these human conditions.

Selected Publications

• Mendelsohn, C., D., Decimo, D., LeMeur, M., Lufkin, T., Chambon, P and Mark M. Specific and redundant developmental functions of retinoic acid receptors alpha, beta and gamma: Malformations of the soft tissues and viscera. Development. 120: 2749-2771 (1994).

• Mendelsohn, C., Mark, M., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., and Chambon, P. Retinoic acid receptor ß2 (RARß2) null mutant mice appear normal. Developmental Biology. 166: 246-258 (1994).

• Mark, M., Lohnes, D., Mendelsohn, C., Dupe, V., Vonesch, J-L., Kastner, P., Rijli, F., Block-Zupan, A., and Chambon, P. Roles of retinoic acid receptors and Hox genes in the patterning of the teeth and of the jaw skeleton. Int. J. Dev. Biol. 39: 111-121 (1995).

• Faria, T.N., Mendelsohn, C., Chambon, P. and Gudas, L.J. The targeted disruption of both alleles of RARb> 2 in F9 cells results in the loss of retinoic acid-associated growth arrest. (1999). J.B.C. 274, 26783-26788.

• Mendelsohn, C., Batourina, K., Fung, S., Gilbert, T. and Dodd, J. Stromal cells mediate retinoid-dependent functions essential for renal development. (1999). Development. 126: 1139-1148.

• Batourina, E., Gim, S., Bello, N., Claggett-Dame, M., Srinivas, S., Costantini, F. and Mendelsohn, C. (2000). Vitamin A controls epithelial/mesenchymal interactions via ret expression.. Nature Genetics, in press.