FIGURE 4.

Schematic depiction of GDNF/RET/GFRα1 signaling in the ureteric bud (UB) tip during kidney development. Gdnf is first expressed in the CM (dark blue) and later also in the surrounding stroma (S, brown). GDNF binds to RET/GRFα1 complex in the UB tip (T, olive green), initiating downstream cascades such as the MAPK and PI3K pathways. Several factors are transcriptionally activated downstream of RET signaling and include Ret itself; Wnt11, which upregulates GDNF; Crlf1, which induces nephrogenesis; and Dusp6 and Spry1, which inhibit RET/GFRα1. ETV4 and -5 are transcription factors mediating the GDNF/RET response to UB epithelium and their expression depends on PI3K signaling. Signaling via the MAPK pathway is important for proliferation, growth, and adhesion, and plays a major role in branching morphogenesis (Moore et al., 1996).