The kidney collecting duct system and the ureter derive from the ureteric bud, an outgrowth of the Wolffian duct. It is generally believed that glial cell-derived neurotrophic factor (GDNF) plays a critical role in this earliest stage of kidney development, but 30 to 50% of knockout mice that lack either Gdnf or one of its receptors, such as Ret, have normal ureters. This suggests that an alternative pathway can induce ureteric bud outgrowth from the Wolffian duct. Isolated Wolffian ducts were cultured, and it was found that a combination of fibroblast growth factor 7 (FGF7) and blockade of the TGF-β superfamily member activin A induced formation of buds from the Wolffian duct. This occurred even in the presence of a neutralizing anti-GDNF antibody or in Ret-knockout-derived Wolffian ducts, suggesting GDNF-independent induction of bud formation. Similar to wild-type ureteric buds or those induced by GDNF, FGF7/follistatin-induced buds were shown to be functionally competent, as they underwent branching morphogenesis and induced nephron formation upon recombination with metanephric mesenchyme. These in vitro findings suggest that modulation by FGF7 and the activin A signaling pathway, or equivalent pathways, can lead to GDNF-independent induction of ureteric bud outgrowth, possibly explaining the seemingly normal ureteric bud outgrowth in Gdnf or Ret null mice.
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