GDNF/Ret signaling and renal branching morphogenesis: From mesenchymal signals to epithelial cell behaviors.

Signaling by GDNF through the Ret receptor tyrosine kinase is required for the normal growth and morphogenesis of the ureteric bud (UB) during kidney development.  Recent studies have sought to understand the precise role of Ret signaling in this process, and the specific responses of UB cells to GDNF.  Surprisingly, the requirement for Gdnf and Ret was largely relieved by removing the negative regulator Spry1, revealing unexpected functional overlap between GDNF and FGF10. However, the kidneys that developed without Gdnf/Ret and Spry1 displayed significant branching abnormalities, suggesting a unique role for GDNF in fine-tuning UB branching.  GDNF/Ret signaling alters patterns of gene expression in UB tip cells, and one critical event is upregulation of the ETS transcription factors Etv4 and Etv5.  Mice lacking Etv4 and Etv5 fail to develop kidneys.  Thus, these genes represent key components of a regulatory network downstream of Ret.  Studies of chimeric embryos in which a subset of cells lack either Ret, Etv4/5 or Spry1 have revealed an important role for this pathway in cell movement.  Ret signaling, via Etv4 and Etv5, promotes competitive cell rearrangements in the nephric duct, in which the cells with the highest level of Ret signaling preferentially migrate to form the first ureteric bud tip.