Nature Genetics
27, 74 - 78 (2001)
doi:10.1038/83792
Vitamin A controls epithelial/mesenchymal interactions through Ret expressionEkatherina Batourina1, Suzanna Gim1, Natalie Bello1, Michael Shy1, Margaret Clagett-Dame3, Shankar Srinivas2, Frank Costantini2
& Cathy Mendelsohn11
Department of Urology, Columbia University, New York, New York, USA. 2
Department of Genetics & Development, Columbia University, New York, New York, USA. 3
Department of Biochemistry and Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Correspondence should be addressed to Cathy Mendelsohn clm20@columbia.eduMutations or rearrangements in the gene encoding the receptor tyrosine kinase RET result in Hirschsprung disease, cancer and renal malformations. The standard model of renal development involves reciprocal signaling between the ureteric bud epithelium, inducing metanephric mesenchyme to differentiate into nephrons, and metanephric mesenchyme, inducing the ureteric bud to grow and branch1,
2. RET and GDNF (a RET ligand) are essential mediators of these epithelial−mesenchymal interactions3. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations4. The vitamin A signal is transduced by nuclear retinoic acid receptors (RARs). We previously showed that two RAR genes, Rara and Rarb2, were colocalized in stromal mesenchyme, a third renal cell type, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth and downregulation of Ret in the ureteric bud5,
6. Here we demonstrate that forced expression of Ret in mice deficient for both Rara and Rarb2 (Rara-/-Rarb2-/-) genetically rescues renal development, restoring ureteric bud growth and stromal cell patterning. Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A−dependent signals secreted by stromal cells control Ret expression in the ureteric bud. In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning.
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