title: Loss of Zeb2 in mesenchyme-derived nephrons causes primary glomerulocystic disease.
abstract: Primary glomerulocystic kidney disease is a special form of renal cystic disorder characterized by Bowman's space dilatation in the absence of tubular cysts. ZEB2 is a SMAD-interacting transcription factor involved in Mowat-Wilson syndrome, a congenital disorder with an increased risk for kidney anomalies. Here we show that deletion of Zeb2 in mesenchyme-derived nephrons with either Pax2-cre or Six2-cre causes primary glomerulocystic kidney disease without tubular cysts in mice. Glomerulotubular junction analysis revealed many atubular glomeruli in the kidneys of Zeb2 knockout mice, which explains the presence of glomerular cysts in the absence of tubular dilatation. Gene expression analysis showed decreased expression of early proximal tubular markers in the kidneys of Zeb2 knockout mice preceding glomerular cyst formation, suggesting that defects in proximal tubule development during early nephrogenesis contribute to the formation of congenital atubular glomeruli. At the molecular level, Zeb2 deletion caused aberrant expression of Pkd1, Hnf1β, and Glis3, three genes causing glomerular cysts. Thus, Zeb2 regulates the morphogenesis of mesenchyme-derived nephrons and is required for proximal tubule development and glomerulotubular junction formation. Our findings also suggest that ZEB2 might be a novel disease gene in patients with primary glomerular cystic disease.
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA; Graduate Program in Genomics and Genetics, Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Hila Milo
authors: HM
authors: Rasouly
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Sudhir
authors: S
authors: Kumar
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Stefanie
authors: S
authors: Chan
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Anna
authors: A
authors: Pisarek-Horowitz
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Richa
authors: R
authors: Sharma
authors: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Qiongchao J
authors: QJ
authors: Xi
authors: Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors: Yuriko
authors: Y
authors: Nishizaki
authors: Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors: Yujiro
authors: Y
authors: Higashi
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: David J
authors: DJ
authors: Salant
authors: Genetics Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Richard L
authors: RL
authors: Maas
authors: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA; Graduate Program in Genomics and Genetics, Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, Massachusetts, USA. Electronic address: wlu@bu.edu.
authors: Weining
authors: W
authors: Lu
mesh_terms: D000818:Animals; D002493:Central Nervous System Diseases / Q000235:genetics*; D004268:DNA-Binding Proteins; D003743:Dental Enamel / Q000002:abnormalities*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D050396:TRPP Cation Channels / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D004268:DNA-Binding Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D050396:TRPP Cation Channels; D015534:Trans-Activators; D000074165:Zinc Finger E-box Binding Homeobox 2; C478000:Glis3 protein, mouse; C496496:Hnf1b protein, mouse; C120602:ZEB2 protein, mouse
keywords: ADPKD; kidney development; obstructive nephropathy; pediatric nephrology; proximal tubule