Further Development 18.2: The Metanephric Mesenchyme Secretes GDNF to Induce and Direct the Ureteric Bud

Intermediate and Lateral Plate Mesoderm: Heart, Blood, and Kidneys

The stage is now set for the secretion of paracrine factors that can induce the ureteric buds to emerge. Under the influence of retinoic acid (which is made in many of the surrounding tissues), the nearby nephric duct is instructed to express the Ret receptor on its cell surfaces (Rosselot et al. 2010). Ret is the receptor for glial-derived neurotrophic factor (GDNF), and GDNF is now secreted from the metanephric mesenchyme. GDNF secreted from the metanephric mesenchyme causes the outgrowth of the ureteric bud from the nephric duct. Indeed, during formation of the ureter, a subset of nephric duct cells (those in which the Ret receptor is most active) migrate to positions closest to the source of GDNF and thus form the tip of the emerging ureteric bud (see Figure 18.7; Chi et al. 2009). Mice whose genes for either GDNF or its receptor are knocked out die soon after birth from renal agenesis (lack of kidneys) (Figure 1; Moore et al. 1996; Pichel et al. 1996; Sánchez et al. 1996). The ability of other regions of the nephric duct to proliferate appears to be suppressed by activin, and one of the major mechanisms of GDNF action may be to locally suppress this inhibitory activin; when activin was experimentally inhibited, numerous ureteric buds formed (Maeshima et al. 2006).

**FIGURE 1** (A) The ureteric bud from an 11.5-day wild-type mouse kidney cultured for 72 hours has a characteristic branching pattern. (B) In embryonic mice heterozygous for a mutation of the gene encoding GDNF, both the size of the kidney and the number and length of its ureteric bud branches are reduced. (C) In mouse embryos missing both copies of the *Gdnf* gene, the ureteric bud does not form. (From Pichel et al. 1996, courtesy of J. G. Pichel and H. Sariola.)

Literature Cited

Chi, X. and 11 others. 2009. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev. Cell 17: 199–209.
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Maeshima, A., D. A. Vaughn, Y. Choi and S. K. Nigam. 2006. Activin A is an endogenous inhibitor of ureteric bud outgrowth from the Wolffian duct. Dev. Biol. 295: 473–485.
PubMed Link

Moore, M. W., R. D. Klein, I. Fariñas, H. Sauer, M. Armanini, H. Phillips, L. F. Reichardt, A. M. Ryan, K. Carver-Moore and A. Rosenthal. 1996. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382: 76–79.
PubMed Link

Pichel, J. G. and 11 others. 1996. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382: 73–76.
PubMed Link

Rosselot, C. and 13 others. 2010. Non-cell-autonomous retinoid signaling is crucial for renal development. Development 137: 283–292.
PubMed Link

Sánchez, M. P., I. Silos-Santiago, J. Frisén, B. He, S. A. Lira and M. Barbacid. 1996. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382: 70–73.
PubMed Link

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