Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells

  1. Joshua T. Mendell1,6,11,12
  1. 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  2. 2Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  3. 3Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  4. 4Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  5. 5Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  6. 6Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  7. 7Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  8. 8Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  9. 9Division of Pathology and Laboratory Medicine, Children's Health, Dallas, Texas 75235, USA;
  10. 10Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  11. 11Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  12. 12Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  1. Corresponding author: joshua.mendell{at}utsouthwestern.edu
  • 13 Present address: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of Dis3l2-null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of Igf2, a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency.

Keywords

Footnotes

  • Received April 17, 2018.
  • Accepted May 23, 2018.

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