Glial Cell–Derived Neurotrophic Factor–Independent Ureteric Bud Outgrowth from the Wolffian Duct

Abstract

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-␤ 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 GDNFindependent 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.

Staged in vitro reconstitution and implantation of engineered rat kidney tissue

“…The recent detection of a GDNF bypass pathway, however, raises the possibility that even GDNF may not **This work performed by David Truong is currently unpublished. be essential for this step (51). Furthermore, a suspended culture system using a diluted Matrigel solution, in addition to the soluble growth factors, is required for the WD devoid of surrounding mesoderm to undergo in vitro budding.…”

The GDNF Target Vsnl1 Marks the Ureteric Tip

“…In vitro and in vivo studies have revealed roles for members of fibroblast growth factor (FGF) family in primary ureteric budding. A combination of FGF7 and follistatin, an inhibitor of activin A, promotes supernumerary UBs from the WD in vitro, 16 and FGF10 alone has the same effect. 17 Genetic models support these results, because mice lacking either Fgf7, Fgf10, 18,19 or Fgfr2 deleted specifically in the ureteric epithelium 20 show renal hypoplasia.…”

The many faces of RET dysfunction in kidney

“…45 Recently, Maeshima et al showed that Fgf7, induced UB outgrowth in Ret null WDs when activin signaling was inhibited. 53 Conclusive evidence for participation of other RTKs in the network of Ret-Spry1 in the early events of WD growth to sculpt the metanephric kidney would require generation of multiple mutant alleles including Fgf pathway mutants, Spry1 and Ret signaling mutants.…”

“…Dr. Sanjay Nigam from UCSD has also shown that if you treat WD derived from Ret knockout animals with FGF7 in presence of inhibitors of activin you can actually induce UB outgrowth further supporting Fgf as an alternate pathway. 53 Jianghui Hou PhD, Assistant Professor of Medicine, Washington University School of Medicine: What is the biochemical basis for the RET signaling? It seems that RET activates PI3 kinase and MAPK kinase, but another kinase pathway upstream (SPRY1-raf) also activates MAPK.…”