O28. Control of branching morphogenesis during kidney development

Signaling by GDNF through the Ret receptor tyrosine kinase is required for the normal formation, growth and branching of the ureteric bud (UB) during kidney development. However, the precise role of GDNF/Ret signaling in this process, and the specific responses of UB cells to GDNF, remain to be fully elucidated. Recent studies provide new insight into the effects of Ret signaling on cell behavior, the functional overlap between GDNF and other growth factors, and the genes functioning downstream of Ret. Lineage studies show that the UB tip cells, which express Ret, are the progenitors for UB growth, while GDNF-expressing mesenchymal cells are the progenitors of nephron epithelia. Time-lapse studies of chimeric embryos reveal that the earliest role of Ret signaling is in the Wolffian duct, where it promotes cell movements that give rise to the first ureteric bud tip. The requirement for GDNF/Ret signaling can be largely relieved by removing the negative regulator Sprouty1, implicating other growth factors, in particular FGF10, in the support of UB growth and branching. However, the kidneys that develop in the absence of GDNF/Ret and Sprouty1 display branching abnormalities, suggesting a unique role for GDNF in determining UB branching pattern. A number of genes whose expression is induced in the UB by GDNF has been identified, including two ETS transcription factors Etv4 and Etv5. These genes are required downstream of Ret for the Wolffian duct cell movements that form the UB tip domain, as well as for later UB growth and branching.