Nephron development

Initiation of nephron development occurs at the termini of the branches of the ureteric bud where cells of the ureteric bud interact with cells of the metanephric mesenchyme. Rather than differentiating in place, analysis of cellular migration indicates that progenitors are recruited from the mesenchyme to the developing epithelial elements of the nephron. The transcriptional program that operates during human nephrogenesis has been mapped in extraordinary detail. WNT9B secreted by the ureteric bud induces a subset of renal progenitor cells to aggregate and express WNT4, which causes the pre-tubular aggregates to further undergo a mesenchymal to epithelial transition to form renal vesicles (inferred from mouse embryos in Park et al. 2007, reviewed in El-Dahr et al. 2008, Costantini and Kopan 2010, Desgrange and Cereghini 2015). A subset of renal progenitor cells express SIX2 and respond to WNT9B by proliferating to maintain a renewing population of renal progenitors. The reason for the difference in responses may be the local concentration of WNT9B (inferred from mouse embryos in Ramalingam et al. 2018) or the presence of the transcription factor SIX2 (inferred from mouse embryos in Karner et al. 2011).

The renal vesicle becomes polarized early. The distal region contains a gene regulatory network containing LHX1, POU3F3 (BRN1), DLL1, and JAG1. LHX1 is required for proximo-distal differentiation (inferred from mouse embryos in Kobayashi et al. 2005) and POU3F3 participates in elongation of the loop of Henle and formation of the distal convoluted tubule (inferred from mouse embryos in Nakai et al. 2003). The proximal region of the renal vesicle expresses WT1, which directly represses PAX2 to enable formation of podocytes (inferred from mouse homologs in Ryan et al. 1995). The renal vesicle develops into the comma-shaped body in which HNF1B in the distal region activates NOTCH pathway components DLL1, JAG1, and LFNG (inferred from mouse embryos in Heliot et al. 2013). The comma-shaped body in turn develops into the S-shaped body in which HNF1B activates IRX1 and IRX2 in the intermediate region (inferred from mouse embryos in Heliot et al. 2013). Podocytes, the proximal tubule, the intermediate tubule, and the distal tubule then differentiate.