Vitamin A controls epithelial/mesenchymal interactions through Ret expression

Abstract

Mutations 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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Figure 1: The cortical stromal cell population is important for generating retinoid-dependent signals required for renal morphogenesis.
Figure 2: Dietary vitamin A controls Ret expression in the ureteric bud.
Figure 3: Vitamin-A–dependent signals control branching morphogenesis and Ret expression in vitro.
Figure 4: A Hoxb7Ret9 transgene rescues renal development in Rara−/−Rarb2−/− mice.
Figure 5: Vitamin A and Ret control a new reciprocal loop between stromal mesenchyme and the ureteric bud epithelium.

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Acknowledgements

We thank Q. Al-awqati, J. Barasch, D. Herzlinger, T. Jessell, A. Pierani, S. Sockanathan and R. Hen for discussions and critical reading of the manuscript; E. Lai and R. Levinson for the Foxd1 probe; S. Sockanathan and T. Jessell for the Raldh2 probe; and P. Chambon for Rara−/−Rarb2−/− mutants. This work was supported by NIH grants to C.M. and F.C.

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Correspondence to Cathy Mendelsohn.

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Batourina, E., Gim, S., Bello, N. et al. Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nat Genet 27, 74–78 (2001) doi:10.1038/83792

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