Abstract
Background Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that transcription factor 21 (Tcf21) is required for ureteric bud branching. Here, we show that Tcf21 in Foxd1+ interstitial progenitors regulates stromal formation and differentiation via interaction with β-catenin. Methods We utilized the Foxd1Cre;Tcf21 f/f murine kidney for morphologic analysis. We used the murine clonal mesenchymal cell lines MK3/M15 to study Tcf21 interaction with Wnt/β-catenin. Results Absence of Tcf21 from Foxd1+ stromal progenitors caused a decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in the Foxd1+ stromal cells also led to defective differentiation of interstitial cells to smooth-muscle cells, perivascular pericytes, and mesangial cells. Foxd1Cre;Tcf21 f/f kidney showed an abnormal pattern of the renal vascular tree. The stroma of Foxd1Cre;Tcf21 f/f kidney demonstrated marked reduction in β-catenin protein expression compared with wild type. Tcf21 was bound to β-catenin both upon β-catenin stabilization and at basal state as demonstrated by immunoprecipitation in vitro. In MK3/M15 metanephric mesenchymal cells, Tcf21 enhanced TCF/LEF promoter activity upon β-catenin stabilization, whereas DNA-binding deficient mutated Tcf21 did not enhance TCF/LEF promoter activity. Kidney explants of Foxd1Cre;Tcf21 f/f showed low mRNA expression of stromal Wnt target genes. Treatment of the explants with CHIR, a Wnt ligand mimetic, restored Wnt target gene expression. Here, we also corroborated previous evidence that normal development of the kidney stroma is required for normal development of the Six2+ nephron progenitor cells, loop of Henle, and the collecting ducts. Conclusions These findings suggest that stromal Tcf21 facilitates medullary stroma development by enhancing Wnt/β-catenin signaling and promotes stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1228-1241 |
| Number of pages | 14 |
| Journal | Kidney360 |
| Volume | 3 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 28 2022 |
Funding
G. Finer is funded by the National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ; K08 A20-0125-001). T. Hayashida is funded by the NIDDK (R01 DK105055-01A1 and NEI 1R01EY030121; Fawzi), S. Ide is funded by an American Heart Association postdoctoral fellowship (20POST35210465). Y. Maezawa is funded by the Japan Society for the Promotion of Science (20H03572). S.E. Quaggin is funded by the NIDDK (R01 DK105055, P30 DK114857, and NEI R01 EY025799). D.R. Winter is supported by funding from the Arthritis National Research Foundation, the American Heart Association (18CDA34110224), the Scleroderma Foundation, the American Lung Association, the American Thoracic Society, the American Federation for Aging, and the National Institutes of Health (U19AI135964). Acknowledgments This work was supported by the Northwestern University Robert H Lurie Comprehensive Cancer Center Core Facilities, including Flow Cytometry Core, Mouse Histology and Phenotyping Laboratory (MHPL) and Center for Advanced Microscopy supported by NCI CCSG P30 CA060553.
Keywords
- Wnt proteins
- basic science
- genetics
- hemodynamics
- renal physiology
- stromal transcription factor 21
- vascular regulation
ASJC Scopus subject areas
- Nephrology
- Medicine (miscellaneous)
- General Medicine