GDNF/Ret signaling and renal branching morphogenesis

Abstract

Signaling by GDNF through the Ret receptor tyrosine kinase is requiredfor the normal growth and morphogenesis of the ureteric bud (UB) duringkidney development. Recent studies have sought to understand the preciserole of Ret signaling in this process, and the specific responses of UBcells to GDNF. Surprisingly, the requirement for Gdnf and Ret waslargely relieved by removing the negative regulator Spry1, revealingunexpected functional overlap between GDNF and FGF10. However, thekidneys that developed without Gdnf/Ret and Spry1 displayed significantbranching abnormalities, suggesting a unique role for GDNF infine-tuning UB branching. GDNF/Ret signaling alters patterns of geneexpression in UB tip cells, and one critical event is upregulation ofthe ETS transcription factors Etv4 and Etv5. Mice lacking Etv4 and Etv5fail to develop kidneys. Thus, these genes represent key components of aregulatory network downstream of Ret. Studies of chimeric embryos inwhich a subset of cells lack either Ret, Etv4/5 or Spry1 have revealedan important role for this pathway in cell movement. Ret signaling, viaEtv4 and Etv5, promotes competitive cell rearrangements in the nephricduct, in which the cells with the highest level of Ret signalingpreferentially migrate to form the first ureteric bud tip.