Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development.
2004
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.
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