Abstract: SA-PO552
Loss of Zeb2 in Ureteric Mesenchymal Cells Causes CAKUT Phenotype in Mice
Session Information
- Developmental Biology
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Developmental Biology and Inherited Kidney Diseases
- 401 Developmental Biology
Authors
- Kumar, Sudhir, Boston University Medical Center, Boston, Massachusetts, United States
- Sharma, Richa, Boston University Medical Center, Boston, Massachusetts, United States
- Fan, Xueping, Boston University Medical Center, Boston, Massachusetts, United States
- Lu, Weining, Boston University Medical Center, Boston, Massachusetts, United States
Background
Congenital anomalies of the kidney and urinary tract (CAKUT) are major causes of renal failure in children. ZEB2 is a SMAD-interacting transcriptional factor that causes Mowat-Wilson Syndrome (MWS), a congenital disorder with an increased risk for CAKUT phenotype including hydroureter and hydronephrosis. However, no defined underlying cellular and molecular mechanisms for hydroureter and hydronephrosis in MWS have been established.
Methods
We generated Zeb2 ureteric mesenchyme-specific conditional knockout mice (Zeb2 cKO) by crossing Zeb2 flox mice with Tbx18Cre mice. Urinary tract phenotypes in Zeb2 cKO mice and their wild-type littermate controls were analyzed by gross and histological examination. ZEB2 expression in developing ureter was analyzed by immunofluorescence staining. Ureteral cellular and molecular phenotypes were studied using cell specific markers, apoptosis assay, and anti-SMAD antibodies.
Results
We found that ZEB2 is highly expressed in the ureteric mesenchymal cells and is co-localized with TBX18 in developing mouse ureter at E14.5. Deletion of Zeb2 flox allele using Tbx18Cre mice leads to hydroureter and hydronephrosis phenotype in E18.5 embryos. At E16.5, Zeb2 cKO mice showed reduced ureteral smooth muscle cells as well as abnormal urothelium morphology compared to wildtype littermates. Immunohistochemical analysis further revealed a downregulation of TBX18 expression in the ureteric mesenchyme in E14.5 Zeb2 cKO mice, indicating abnormal ureteric mesenchyme development. We also found increased apoptosis and upregulation of pSMAD1/5/8 expression in ureteric mesenchyme cells in E14.5 Zeb2 cKO, suggesting loss of ureteric mesenchymal cells and abnormal SMAD signaling in developing ureter.
Conclusion
ZEB2 is required for normal ureteric mesenchymal cell development. Loss of Zeb2 in ureteric mesenchymal cells leads to reduced TBX18+ mesenchymal cells and abnormal ureteral smooth muscle formation due to aberrant SMAD signaling, which eventually causes hydroureter and hydronephrosis in Zeb2 cKO mice.
Funding
- NIDDK Support