title: Transcriptional dysregulation in the ureteric bud causes multicystic dysplastic kidney by branching morphogenesis defect.
abstract: OBJECTIVE
  The calcineurin-NFAT signaling pathway regulates the transcription of genes important for development. It is impacted by various genetic and environmental factors. We investigated the potential role of NFAT induced transcriptional dysregulation in the pathogenesis of congenital abnormalities of the kidneys and urinary tract.
  
  
  METHODS
  A murine model of conditional NFATc1 activation in the ureteric bud was generated and examined for histopathological changes. Metanephroi were also cultured in vitro to analyze branching morphogenesis in real time.
  
  
  RESULTS
  NFATc1 activation led to defects resembling multicystic dysplastic kidney. These mutants showed severe disorganization of branching morphogenesis characterized by decreased ureteric bud branching and the disconnection of ureteric bud derivatives from the main collecting system. The orphan ureteric bud derivatives may have continued to induce nephrogenesis and likely contributed to the subsequent formation of blunt ended filtration units and cysts. The ureter also showed irregularities consistent with impaired epithelial-mesenchymal interaction.
  
  
  CONCLUSIONS
  This study reveals the profound effects of NFAT signaling dysregulation on the ureteric bud and provides insight into the pathogenesis of multicystic dysplastic kidney. Our results suggest that the obstruction hypothesis and the bud theory may not be mutually exclusive to explain the pathogenesis of multicystic dysplastic kidney. Ureteric bud dysfunction such as that induced by NFAT activation can disrupt ureteric bud-metanephric mesenchyma interaction, causing primary defects in branching morphogenesis, subsequent dysplasia and cyst formation. Obstruction of the main collecting system can further enhance these defects, producing the pathological changes associated with multicystic dysplastic kidney.
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Qiusha
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Piyush
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manson
authors.affiliation: Division of Urology, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Austin
authors.affiliation: Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address: fchen@dom.wustl.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D051379:Mice; D021782:Multicystic Dysplastic Kidney / Q000196:embryology*; D050778:NFATC Transcription Factors / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D014513:Ureter / Q000196:embryology*
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D019703:Calcineurin
keywords: NFAT transcription factors; etiology; kidney; morphogenesis; organogenesis