Genetic controls and cellular events during renal branching morphogenesis

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During kidney development, the ureteric bud (UB), an outgrowth from the nephric duct, elongates and branches repeatedly to give rise to the renal collecting system. This process is stimulated by GDNF signaling via Ret receptor tyrosine kinase and transcription factors Etv4 and Etv5. Inducible genetic fate mapping showed that UB tip cells, which specifically express Ret and Etv4/Etv5, are progenitors for the growing collecting ducts. To investigate how the behaviors of these cells are influenced by Ret – Etv4/5 signaling, we first performed time-­‐lapse imaging of genetically mosaic organ cultures. These studies revealed that Ret signaling, via Etv4 and Etv5, promotes competitive cell rearrangements, which cause a subset of cells in the nephric duct to form the first UB tip. To ask whether similar cell rearrangements contribute to UB branching, we performed clonal analyses, using several methods to induce fluorescently labeled, recombinant clones in which the gene dosage of Ret or Etv4 was altered. Analysis of such clones, in time-­‐lapse movies of developing kidneys, indicate that the Ret – Etv4/5 pathway controls epithelial cell movements, which maintain the tip (progenitor) cell population and may promote epithelial branching.