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Abstract: FR-OR14

ZEB2 Signaling Is Essential for Ureteral Smooth Muscle Cell Differentiation and Maintenance

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Kumar, Sudhir, Boston University, Boston, Massachusetts, United States
  • Fan, Xueping, Boston University, Boston, Massachusetts, United States
  • Zaltz, Emily, Boston University, Boston, Massachusetts, United States
  • Song, Paul, Boston University, Boston, Massachusetts, United States
  • Jiang, Yuqiao, Boston University, Boston, Massachusetts, United States
  • Lu, Weining, Boston University, Boston, Massachusetts, United States
Background

Mowat-Wilson Syndrome (MWS) is an autosomal dominant complex disorder caused by mutations in the ZEB2 that plays a critical role in cell fate determination and differentiation during development. Congenital anomalies of the kidney and urinary tract (CAKUT), such as hydroureter and hydronephrosis, have been reported in MWS patients. However, the role of ZEB2 in urinary tract development and the cellular and molecular mechanism underlining the CAKUT phenotype in MWS remains unknown.

Methods

We performed ZEB2 protein expression analysis in the developing mouse ureter. We generated Zeb2 ureteral mesenchyme-specific conditional knockout mice by crossing Zeb2 floxed mice with Tbx18Cre mice (Zeb2 cKO) and analyzed the urinary tract phenotypes in Zeb2 cKO mice and their wild-type littermate controls by gross and histological examination. Ureteral cellular and molecular phenotypes were studied using cell-specific markers such as TAGLN, ACTA2, FOXD1, POSTN, CDH1, TBX18, and SOX9.

Results

We found that ZEB2 is expressed in TBX18+ ureteral mesenchymal cells at E14.5 and E15.5 during mouse fetal development. Deletion of Zeb2 in developing ureteral mesenchymal cells causes hydroureter and hydronephrosis phenotypes, leading to obstructive uropathy, kidney failure, and early mortality. Cellular and molecular marker analyses showed that the TAGLN+ and ACTA2+ ureteral smooth muscle cells (SMCs) layer is not formed in Zeb2 cKO mice at E15.5, but the FOXD1+ and POSTN+ tunica adventitia cells layer is significantly expanded compared to wild-type littermate controls. CDH1+ urothelium cells are reduced considerably in the Zeb2 cKO ureters at E15.5. Mechanistically, we found that Zeb2 cKO mice have significantly decreased TBX18 expression but an increased SOX9 expression in the developing ureter at E14.5 and E15.5 compared to wild-type littermate controls.

Conclusion

Our results show that ZEB2 is essential for mouse ureter development by maintaining ureteral mesenchymal cell differentiation into normal ureteral SMCs. Our study also shed new light on the pathological mechanism underlying the developmental abnormalities of the urinary tract and CAKUT phenotype in MWS patients.

Funding

  • NIDDK Support