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 branch. 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. 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. 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.

The RET oncogene is a critical component of transcriptional programs associated with retinoic acid–induced differentiation in neuroblastoma

“…It participates in a reciprocal loop between stromal mesenchyme and the ureteric bud epithelium; vitamin Adependent signals secreted by stromal cells control Ret expression in the ureteric bud. Ureteric bud signals dependent on Ret then control stromal cell patterning (54). RET expression within the differentiating metanephros may control the nephron mass (55), and increased RET expression occurs before neurite outgrowth in neuroblastic cells induced with RA (56).…”

GDNF/Ret signaling and the development of the kidney

“…(30,60,61) The same is true of mutations in retinoic acid receptors, whose expression is required for the maintenance of Ret expression, and which can be rescued by forced expression of Ret in the UB. (10) Addition of GDNF to kidney cultures can increase the number of UB tips, which suggested a stimulation of branching. (42,62) Conversely, GDNF antibodies (42,63) or a Ret-Ig fusion protein (64) inhibit growth of the kidney in vitro.…”

“…(5)(6)(7)(8) It has long been believed that the MM controls many aspects of UB growth and branching through inductive interactions and, more recently, it has been learned that the renal stroma, which is derived from a distinct cell population in the metanephric blastema, is also important for normal UB development. (9)(10)(11)(12) A number of growth factors expressed by the MM and/or stromal cells or the UB itself, including members of the FGF, TGF-b and Wnt families, have been implicated in the control of UB branching morphogenesis. Other cell surface and extracellular matrix proteins such as integrins, heparan sulfate proteoglycans and matrix metalloproteases also appear to play roles in branching morphogenesis in the kidney as well as in other organs.…”

Genetic Regulation of Branching Morphogenesis: Lessons Learned from Loss-of-Function Phenotypes

“…Transgenic overexpression of Ret in these mice rescues branching morphogenesis (14). At least two members of the FGF family of signaling peptides stimulate collecting duct morphogenesis in mice.…”