Figure 7.
Key players in the network of assumed Foxd2 (forkhead boxD2) function. Although Foxd1 expression in the developing mouse kidney is largely restricted to the mesenchymal stroma, Foxd2 is found in the cap mesenchyme where it plays a role in Pax2 expression.10,74 Foxd2 dysfunction leads to reduced PAX2 protein levels (see the Results section and Figure 6b and c). Eya1 is important for Pax2 expression in the ureteric bud–induced metanephric mesenchyme (embryonic day 11.5 in the mouse), and Eya1 upregulation in Foxd2 mutant cells may indicate a compensatory mechanism for reduced Pax2 expression via a feedback loop.76Pax2 activates Wnt4 expression in the metanephric mesenchyme during mammalian kidney development, and Wnt4 expression is downregulated in Foxd2 mutant cells.70Pax2 enhances Emx2 gene expression, and Emx2 expression is downregulated in Foxd2 mutant cells.61 Nephron progenitor cells lacking Pax2 can change into Foxd1-positive renal interstitium–like cell types, suggesting that Pax2 represses a renal interstitial cell program.62 This is supported by the upregulation of Fat4 in Foxd2 mutant cells as Fat4 encodes an atypical cadherin expressed by stromal cells inhibiting nephron progenitor renewal.64Fgfr2 (and Fgfr1) is believed to act downstream of Eya1 and upstream of Pax2 in the metanephric mesenchyme.77 Conditional knockout of Fgfr2 in metanephric mesenchyme cells leads to congenital anomalies of the kidney and urinary tract in mice and deficiency of Fgfr2 in stromal cells69 (see Discussion for further details). Adapted from McMahon AP. Development of the mammalian kidney. Curr Top Dev Biol. 2016;117:31–6474 and Walker KA, Sims-Lucas S, Bates CM. Fibroblast growth factor receptor signaling in kidney and lower urinary tract development. Pediatr Nephrol. 2016;31:885–895.75