DLG1 influences distal ureter maturation via a non-epithelial cell autonomous mechanism involving reduced retinoic acid signaling, Ret expression, and apoptosis.
The absence of Discs-large 1 (DLG1), the mouse ortholog of the Drosophila discs-large tumor suppressor, results in congenital hydronephrosis characterized by urinary tract abnormalities, reduced ureteric bud branching, and delayed disconnection of the ureter from the common nephric duct (CND). To define the specific cellular requirements for Dlg1 expression during urogenital development, we used a floxed Dlg1 allele and Pax2-Cre, Pax3-Cre, Six2-Cre, and HoxB7-Cre transgenes to generate cell type-restricted Dlg1 mutants. In addition, we used Ret(GFP) knockin and retinoic acid response element-lacZ transgenic mice to determine the effects of Dlg1 mutation on the respective morphogenetic signaling pathways. Mutation of Dlg1 in urothelium and collecting ducts (via HoxB7-Cre or Pax2-Cre) and in nephron precursors (via Pax2-Cre and Six2-Cre) resulted in no apparent abnormalities in ureteric bud branching or in distal ureter maturation, and no hydronephrosis. Mutation in nephrons, ureteric smooth muscle, and mesenchyme surrounding the lower urinary tract (via the Pax3-Cre transgene) resulted in congenital hydronephrosis accompanied by reduced branching, abnormal distal ureter maturation and insertion, and smooth muscle orientation defects, phenotypes very similar to those in Dlg1 null mice. Dlg1 null mice showed reduced Ret expression and apoptosis during ureter maturation and evidence of reduced retinoic acid signaling in the kidney. Taken together, these results suggest that Dlg1 expression in ureter and CND-associated mesenchymal cells is essential for ensuring distal ureter maturation by facilitating retinoic acid signaling, Ret expression, and apoptosis of the urothelium.
Renal Division, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Sung Tae
ST
Kim
Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Pediatrics, Children׳s National Medical Center and the George Washington University, Washington, DC 20010, USA.
Sun-Young
SY
Ahn
Department of Pathology & Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Wojciech
W
Swat
Renal Division, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: minerj@wustl.edu.
Jeffrey H
JH
Miner
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D000074288:Discs Large Homolog 1 Protein; D005455:Fluorescent Antibody Technique; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000074407:SAP90-PSD95 Associated Proteins; D015398:Signal Transduction / Q000502:physiology*; D059008:Time-Lapse Imaging; D014212:Tretinoin / Q000378:metabolism*; D014343:Trypan Blue; D014513:Ureter / Q000196:embryology*
D017931:DNA Primers; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; D014212:Tretinoin; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D014343:Trypan Blue
Hydronephrosis; PDZ domain; Urogenital system