Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development

The kidney is a classic model for studying mechanisms of inductive tissue interactions associated with the epithelial branching common to many embryonic organs, but the molecular mechanisms are still poorly known. Sprouty proteins antagonize tyrosine kinases in the Egf and Fgf receptors and are candidate components of inductive signalling in the kidney as well. We have addressed the function of sprouty proteins in vivo by targeted expression of human sprouty 2 (SPRY2) in the ureteric bud, which normally expresses inductive signals and mouse sprouty 2 (Spry2). Ectopic SPRY2 expression led to postnatal death resulting from kidney failure, manifested as unilateral agenesis, lobularization of the organ or reduction in organ size because of inhibition of ureteric branching. The experimentally induced dysmorphology associated with deregulated expression of Wnt11, Gdnf and Fgf7 genes in the early stages of organogenesis indicated a crucial role for sprouty function in coordination of epithelial-mesenchymal and stromal signalling, the sites of expression of these genes. Moreover, Fgf7 induced Spry2 gene expression in vitro and led with Gdnf to a partial rescue of the SPRY2-mediated defect in ureteric branching. Remarkably, it also led to supernumerary epithelial bud formation from the Wolffian duct. Together, these data suggest that Spry genes contribute to reciprocal epithelial-mesenchymal and stromal signalling controlling ureteric branching, which involves the coordination of Ffg/Wnt11/Gdnf pathways.     

Wnt signaling in kidney development and disease

The Wnt gene family, which encodes secreted growth and differentiation factors, has been implicated in kidney organogenesis. The Wnts control both ureteric bud development and signaling, but they also serve as inductive factors to regulate nephrogenesis in the mesenchcymal cells. Several of the Wnt genes are expressed in the developing kidney, and gene knock-out studies have revealed specific developmental functions for these. Consistent with this, changes in Wnt ligands and pathway components are associated with many kidney diseases, including kidney cancers, renal fibrosis, cystic kidney diseases, acute renal failure, diabetic nephropathy and ischaemic injury. It is these associations of the Wnt signaling system with kidney development and kidney diseases that form to topic of this review.Key words: Wnt signaling, tubule induction, ureter development, kidney diseases, kidney cancer     

Wnts as kidney tubule inducing factors.

Since the discovery that inductive tissue interactions regulate nephrogenesis, one of the aims has been to identify the molecules that mediate this induction. The small size of embryonic tissue has limited the possibilities to identify the inducers biochemically, even though such efforts were directed to study, e.g. neural induction (for a comprehensive review, Saxén and Toivonen, Primary embryonic induction, Academic Press, London, 1962). The rapid progress in molecular biology made it possible to identify genes from minute amounts of tissue and provided techniques to generate recombinant proteins to assay their action in classic experimental systems. This led to the identification of some signals that are involved in primary and secondary inductive interactions during embryogenesis. Here, we will review evidence suggesting that secreted signaling molecules from the Wnt gene family mediate kidney tubule induction.