The kidney and the collecting system originate from the interaction between the mesonephric duct (Wolffian duct) and the metanephric mesenchyme (MM). The uretic bud (UB) forms as an epithelial outpouching from the mesonephric duct and invades the surrounding MM. Reciprocal induction between the UB and MM results in branching and elongation of the UB from the collecting system and in condensation and epithelial differentiation of MM around the branched tips of the UB. Branching of the UB occurs approximately 15 times during human renal development, generating approximately 300,000 and 1 million nephrons per kidney (Nyengaard and Bendtsen, 1992).
This process of reciprocal induction is dependent on the expression of specific factors. Glial cell–derived neurotrophic factor (GDNF) is the primary inducer of ureteric budding (Costantini and Shakya, 2006). GDNF interacts with several different proteins from the MM (eg, Wt-1, Pax2, Eyal, Six1, Sall 1) and from the UB itself (Pax2, Lim1, Ret) resulting in outgrowth of the UB (reviewed by Shah et al, 2004). Proper activation of the Ret/GDNF signaling pathway in the tip of UB epithelium appears to be essential in the progression of branching morphogenesis (reviewed by Michos, 2009). B-catenin and Gata-3 are important regulators of Ret expression, and correct activity of Ret is regulated by positive (Wnt-11 from MM) and negative (Sprouty1 from the UB) feedback signaling. Additional specific factors are required for (1) early branching (eg, Wnt-4 and 11, fgf 7–10); (2) late branching and maturation (bmp2, activin); and (3) branching termination and tubule maintenance (hepatocyte growth factor, transforming growth factor-alpha, epidermal growth factor receptor) (reviewed by Shah et al, 2004). BMP-7, SHH, and Wnt-11 produced from the branching ureteric bud induce the MM to differentiate. These factors induce the activation of Pax2, alpha-8-integrin, and Wnt-4 in the renal mesenchymal cells, resulting in condensation of the MM and the formation of pretubular aggregate and primitive renal vesicle (reviewed by Burrow, 2000). With the continued induction from the UB and the autocrine activity of Wnt-4, the pretubular aggregates differentiate into comma-shaped bodies. Platelet derived growth factor alpha-beta and vascular endothelial growth factor expression are required for initiating the migration of endothelial cells into the cleft of the comma-shaped bodies to form rudimentary glomerular capillary tufts (reviewed by Burrow, 2000). Wt-1 and Pod-1 may have important functions in the regulation of gene transcription necessary for the differentiation of podocytes (Ballermann, 2005).