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Abstract: PO1263

Six2Cre-Mediated Deletion of Anks6 leads to Proximal Tubule Developmental Defects

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Airik, Rannar, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Huynh, Amy B., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Airik, Merlin, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of autosomal recessive kidney diseases that are characterized by renal cysts, tubulointerstitial fibrosis and basement membrane disruptions. Mutations in ankryrin repeat and sterile alpha motif domain containing 6 (ANKS6) gene were recently identified as causing nephronophthisis type 16 (NPHP16) in humans. Although, several mouse models with Anks6 mutations have been reported, its function in the kidney remains incompletely understood. In order to investigate the disease mechanisms of nephronophthisis and the function of Anks6 in kidneys we deleted Anks6 expression in the nephron progenitor population using the Six2Cre transgenic mouse line.


Six2Cre transgenic mice were crossed with Anks6fl/fl mice to generate Six2Cre;Anks6fl/fl mice. Gross morphological characterization and tissue histological analysis of mutant mice was performed on E15.5, E18.5 and P1 kidneys. Kidneys were embedded in paraffin and sectioned at 5μm thickness for histological staining with hematoxylin and eosin. Immunofluorescence (IF) staining was performed to label nephron segments and glomerular components. Anks6 expression in the kidney was examined using X-gal staining. ANKS6 role in epithelial cell polarity was investigated using a spheroid assay after ANKS6 siRNA knockdown in IMCD3 cells.


Six2Cre;Anks6fl/fl mice die at birth due to kidney failure. Anks6 expression was ubiquitous in the developing kidney. Histological analysis revealed that deletion of Anks6 in nephron progenitors leads to proximal tubule morphogenesis defects and glomerular cysts. Immunostaining of the glomeruli showed reduced recruitment of mesangial cells and decreased poodcyte numbers in mutant kidneys. Proximal tubule development was similarly arrested at an early tubular morphogenesis stage resulting in short straight tubules. Knock down of ANKS6 in cell culture resulted in polarization and lumen formation defects.


Our data demonstrate that Anks6 is required for proximal tubule morphogenesis and glomerular development. Deletion of Anks6 in nephron progenitors leads to severe kidney morphogenesis defects that are incompatible with life. Spheroid assay revealed that ANKS6 has an important role in epithelial polarity and lumen formation. Future work will address which morphogenic pathway(s) are regulated by Anks6 during nephrogenesis.


  • NIDDK Support