FIGURE 1.

(A) Ureteric bud branching morphogenesis is cooperatively regulated by FGF10 and GDNF via Etv4 and Etv5, whereas Sprouty1 acts as a negative regulator of FGF10 and GDNF signalling downstream of FGFR2 and RET. (1) Regulation of UB branching in the wild type: GDNF is the main promoting factor for UB outgrowth and branching, while FGF10 plays a minor role. Sprouty1 counteracts ligand-receptor signalling, resulting in the development of a normal kidney. (2) The absence of GDNF abrogates UB branching and UB outgrowth, resulting in kidney agenesis or severe hypodysplasia. (3) If both the negative regulator Sprouty1 and GDNF are absent FGF10 signalling is sufficient to drive Etv4/Etv5 expression, allowing for UB branching and kidney development. The branching pattern differs from the wild type, which points to a GDNF specific regulation of UB morphogenesis. (4) In the triple knockout, there is not enough ligand-receptor signalling to drive UB outgrowth and branching, even though Sprouty1 is absent as well. (5) Increased receptor tyrosine kinase signalling resulting from the absence of Sprouty1 does not rescue the renal agenesis phenotype of Etv4 -/- Etv5 -/- mice. In this triple knockout, the UB grows out, but fails to undergo branching and only ureters develop, suggesting that branching morphogenesis is dependent on Etv4 and Etv5. The insets in 1 and 3 show the pattern of UB tips on the surface of P0 wild type and double mutant kidneys. Reproduced with permission from Michos et al. (2010). (B) Gene expression domains of Fgf10 and Gdnf and their receptors in the developing lung and kidney at E11.5. In the lung, Fgf10 is expressed in the submesothelial mesenchyme in a spotty fashion opposed to growing buds. Fgfr2b is expressed in the lung epithelium. In the kidney, Fgf10 and Gdnf are expressed in the metanephric mesenchyme. Fgfr2 is expressed both in the mesenchyme and the epithelium, whereas Ret is restricted to the branch tips (ampulla). Expression domains are colour coded as indicated.