Abstract: FR-PO754
ZEB2 Controls Ureteral Smooth Muscle Cell Fate
Session Information
- Development and Organoid Models
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Kumar, Sudhir, Boston University, Boston, Massachusetts, United States
- Lara, Brian D., Boston University, Boston, Massachusetts, United States
- Pydi, Aneesha, Boston University, Boston, Massachusetts, United States
- Fan, Xueping, Boston University, Boston, Massachusetts, United States
- Lu, Weining, Boston University, Boston, Massachusetts, United States
Background
ZEB2 is a SMAD-interacting transcriptional factor and loss-of-function ZEB2 mutations are associated with Mowat-Wilson Syndrome (MWS), a genetic disease with multiple congenital defects including hydroureter and hydronephrosis. Ureteral smooth muscle cells (SMCs) derive from TBX18+ mesenchymal progenitors and abnormal development of ureteral SMCs can lead to hydroureter and hydronephrosis. However, the molecular role of ZEB2 in ureteral SMCs development from TBX18+ mesenchymal progenitors is not known.
Methods
We analyzed Zeb2 ureteral mesenchyme-specific conditional knockout mice Zeb2flox/flox;Tbx18Cre+ (Zeb2 cKO) and their wild-type littermate controls for urinary tract phenotypes by gross and histological examination. Cell specific marker studies were carried out to determine abnormal ureteral cellular and molecular phenotypes and ureteral SMCs development.
Results
We found that at P0 and E16.5, Zeb2 cKO mice developed hydroureter and hydronephrosis with dilated ureter devoid of ureteral smooth muscle cells as compared to wild-type littermate controls. Cell marker study showed that TAGLN+ACTA2+ ureteral SMCs did not appear but there was an expanded layer of FOXD1+POSTN+ ureteral tunica adventitia in Zeb2 cKO mice during early ureter development. At E14.5-E15.5, there was an increase in SOX9 expression in ureteral mesenchymal cells but a decrease in TBX18 expression in Zeb2 cKO mice, suggesting an early abnormal development of ureteral SMCs. We also found that both apoptosis and proliferation were increased in ureteral mesenchyme cells, and the SMAD signaling was disturbed in Zeb2 cKO mice.
Conclusion
ZEB2 is expressed in ureteral mesenchymal cells. In the absence of ZEB2, ureteral inner mesenchymal cells differentiate into FOXD1+POSTN+ ureteral tunica adventitia rather than ureteral SMCs. These data suggest that ZEB2 controls ureteral smooth muscle cell fate in ureteral mesenchymal cells. Loss of ZEB2 leads to depletion in the ureteral smooth muscle layer formation, which eventually causes hydroureter and hydronephrosis phenotype in Zeb2 cKO mice.
Funding
- NIDDK Support