Journal
NATURE GENETICS
Volume 27, Issue 1, Pages 74-78Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/83792
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK061459, R56DK082963] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R01 DK061459-07, R56 DK082963, R01 DK061459-06, R56 DK082963-01, R01 DK061459, R01 DK061459-09, R01 DK061459-07S1, R01 DK061459-08, R01 DK061459-05] Funding Source: Medline
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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 branch(1,2). RET and GDNF (a RET ligand) are essential mediators of these epithelial-mesenchymal interactions'. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations(4), 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 bud(5,6). 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 Rot control stromal cell patterning.
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