Bowman's β-Catenin

Wnt/β-catenin signaling plays a significant role during kidney development and maturation.1–3β-Catenin, the canonical Wnt signal transducer, is involved in nephron induction4,5 and branching morphogenesis.1,6 Importantly, β-catenin modulation is necessary for full differentiation of the induced nephron as it proceeds through morphogenesis.4 These observations demonstrate β-catenin activity is used in both the positive and negative to convey patterning and cell fate information and that its actions are reused in different contexts. Aberrations in Wnt/β-catenin signaling may also contribute to dysplasia.7,8 In this issue of JASN, Grouls et al.9 describe a late role for β-catenin in the formation of the parietal epithelial cells (PECs) of Bowman's capsule. Using TCF/lacZ reporter mice,10 the authors observed Wnt/β-catenin reporter activity in the parietal epithelial cells of Bowman's capsule, suggesting a role for its action in these cells. By using a Pax8.Cre driver line that is active at the S-shaped body stage of developing nephrons, and therefore after the initial induction of nephron formation, they conditionally removed β-catenin to examine its subsequent role in maturation. They observed the loss of β-catenin at the S-shaped body stage results in the absence of PECs in the renal corpuscles and instead, Bowman's capsule was populated with parietal podocytes. These cells were positive for podocyte markers (WT1, synaptopodin, and vascular endothelial growth factor), induced the formation of additional capillaries, and established a near identical structure to the glomerular podocyte-endothelium including foot processes. Because the PECs and podocytes arise from a common cellular origin, the renal vesicle/S-shaped body, these findings suggest β-catenin is required for cells to adopt the PEC fate rather than the podocyte fate. In the absence of β-catenin, the cells default to podocytes. Mutant mice lacking PECs had reduced survival starting at 2 weeks of age and showed progressive renal disease. This raises a question about the role of PECs in the renal corpuscle of older animals. In recent work by Appel et al.,11 cell lineage tracing reveals the PECs of Bowman's capsule as a source of replacement podocytes when some are lost from the glomerulus of healthy or injured kidneys.12 Ranconi et al.13 also describe a resident progenitor cell around the urinary pole of Bowman's capsule and suggest these replace podocytes and proximal tubular cells lost through cell turnover or injury. Additionally, it has been shown by others that Tgf-β induces glomerular injury by inducing expression of Wnt1 that increases activated β-catenin.14 This results in depression of WT1 in a response that may be a perturbation of the response mechanism of the renal corpuscle—that is, to dedifferentiate (decrease WT1) and proliferate in an effort to replace damage cells.14 One can imagine a model where Wnt/β-catenin signaling maintains the dividing parietal cells, and some of these cells exit this niche to replace failed podocytes. This is consistent with the role of Wnt/β-catenin in other adult tissues, notably the intestinal crypts surrounding each villus. In the adult intestine, Wnt/β-catenin signaling is required for stem cell maintenance and cell proliferation in the lower crypt, and some of these cells eventually exit the crypt and differentiate to replace cells lost in the villus.15 A similar activity in the renal corpuscle is not yet clear. The Wnt/β-catenin reporter mouse strains exhibit some variability in identifying active signaling.16 For example, the TCF/lacZ strain lacks detectable staining after nephrogenesis in complete,10 whereas the TOPGAL and Axin2-lacZ strains show staining at least in the medullary region of the adult kidney.17 Therefore, a close examination of Wnt/β-catenin target gene expression in the PECs of adults would be useful to confirm or eliminate the possibility of signaling activity. It would also be interesting to inactivate the β-catenin gene using the genetic system used by Appel et al.11 This would address the requirement of β-catenin for maintaining PECs and for responding to adriamycin injury.13,14 As we learn more about the developmental roles of these important pathways, we also begin to see how they may be used in maintenance systems of organs and tissues. Combined with recent data on the role of senescent cells in age-related pathogenesis,18 there is more work to be done here to understand how we may influence normal tissue renewal to aid failing kidneys and identify genes that indicate risk for certain patterns of injury. DISCLOSURES None.