INTRODUCTION The development of the mammalian kidney, or metanephros, occurs in a region of posterior intermediate mesoderm by inductive interactions between the metanephric mesenchyme and the ureteric bud epithelium (Kuure

The development of the mammalian kidney, or metanephros, occurs in a region of posterior intermediate mesoderm by inductive interactions between the metanephric mesenchyme and the ureteric bud epithelium (Kuure et al., 2000; Lechner and Dressler, 1997; Schedl and Hastie, 2000). Induction of the mesenchyme by signals emanating from the bud initiates the aggregation of the mesenchyme and the conversion of these aggregates to the tubular epithelial cells of the nephron. Reciprocally, signals from the mesenchyme induce the ureteric bud to proliferate and undergo branching morphogenesis, thus generating much of the collecting duct system. The ureteric bud is an outgrowth of the posterior nephric duct, a bilateral epithelial duct, that extends longitudinally along much of the anteroposterior body axis. In the mouse, outgrowth and extension of the ureteric bud begins at embryonic day 10.5 in that region of the nephric duct directly adjacent to a group of predetermined mesenchymal cells, which correspond to the metanephric mesenchyme. Ureteric bud growth is regulated by glial-cell derived neurotrophic factor (GDNF) (Sainio et al., 1997; Vega et al., 1996) and its receptors, the Gi-linked protein GFRα1 (Gfra1 – Mouse Genome Informatics) (Cacalano et al., 1998) and the RET tyrosine kinase (Schuchardt et al., 1994; Schuchardt et al., 1996). At that time, GDNF is expressed in the posterior intermediate mesoderm, the presumptive metanephric mesenchyme, whereas RET localizes to the nephric duct (Pachnis et al., 1993). GFRα1 is expressed in both mesenchymal and epithelial compartments of the developing kidney (Sainio et al., 1997). Mice homozygous for null mutations in Ret (Schuchardt et al., 1994), Gfra1 (Cacalano et al., 1998) or Gdnf (Moore et al., 1996; Pichel et al., 1996; Sanchez et al., 1996) exhibit similar phenotypes, with near complete renal agenesis caused by a block in ureteric bud outgrowth. GDNF can activate the catalytic domain of RET and stimulate branching morphogenesis of the ureteric bud (Vega et al., 1996). Indeed, GDNF can function as a chemoattractant for RET-expressing epithelial cells (Tang et al., 1998). Thus, GDNF is a target-derived guidance cue that assures correct outgrowth and invasion of the ureteric bud into the metanephric mesenchyme. Failure to control the position of ureteric bud growth and subsequent branching morphogenesis can underlie a variety of syndromes, from complete renal agenesis to more subtle defects, such as double or bifurcated ureters, vesicoureteral reflux, or CAKUT (Pope et al., 1999). 4747 Development 128, 4747-4756 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 DEV9791