Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1), causes defects in kidney development in mice. Spry1(-/-) embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.

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From a wealth of experimental findings, derived from both in vitro and in vivo experiments, it is becoming clear that fibroblast growth factors regulate processes that are central to all aspects of nervous system development. Some of these functions are well known, whereas others, such as the roles of these proteins in axon guidance and synaptogenesis, have been established only recently. The emergent picture is one of remarkable economy, in which this family of ligands is deployed and redeployed at successive developmental stages to sculpt the nervous system.