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Abstract: PO0610

Stromal Transcription Factor 21 Is Critical for Development of the Interstitium and Nephron Progenitor Cells via Interaction with Wnt/β-Catenin Signaling

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Finer, Gal, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Maezawa, Yoshiro, Chiba Daigaku, Chiba, Chiba, Japan
  • Ide, Shintaro, Duke University, Durham, North Carolina, United States
  • Onay, Tuncer, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Souma, Tomokazu, Duke University, Durham, North Carolina, United States
  • Winter, Deborah R., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hayashida, Tomoko, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Reciprocal signaling between the collecting duct progenitors and the nephron progenitor cells (NPC) is the primary driver for kidney development. In addition, recent studies implicate input from the interstitial progenitor cells in multiple aspects of kidney development. However, the mode of insterstitial cell action on kidney development is poorly understood. We previously showed that the Transcription factor 21 (Tcf21) in interstitial progenitors is required for normal ureteric bud branching. Here, we examined roles for Tcf21 in renal interstitial progenitors in mediating stromal functions during kidney development.

Methods

Stromal Tcf21 was evaluated with the Foxd1Cre;Tcf21f/f or +/+ mouse kidney by standard immunohistological analyses. MK3 and M15 metanephric mesenchymal cell lines were used for analyses of b-catenin signaling.

Results

In the Foxd1Cre;Tcf21f/f kidney, absence of Tcf21 from Foxd1+ stromal progenitors caused decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in FoxD1 stromal cells also led to defective differentiation to perivascular cells and mesangial cells. Non-autonomously, absence of stromal Tcf21 led to expansion of the Six2+ NPC, suggestive of delayed NPC differentiation, and to poor development of the Loop of Henle and the collecting ducts. We next examined whether Tcf21 modulates Wnt/ β-catenin signaling. Significantly less β-catenin was observed in stroma of the Foxd1Cre;Tcf21f/f mouse compared to their wild-type littermates. In MK3 and M15 cells, stabilization of β-catenin by Lithium Chloride upregulated Tcf21 expression, while over-expression of Tcf21 enhanced expression of Wnt-target genes upon β-catenin stabilization. Further, Tcf21 enhanced TCF/LEF reporter activity upon β-catenin stabilization, while mutated-Tcf21 failed to increase TCF/LEF activity. Immunoprecipitation assay showed that Tcf21 is bound to β-catenin at basal and activated states in-vitro.

Conclusion

Together, our findings suggest that Stromal-Tcf21 is essential for medullary stroma development, by enhancing Wnt/ β-catenin signaling to promote stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.

Funding

  • NIDDK Support