Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells
- Ryan W. Hunter1,2,
- Yangjian Liu1,13,
- Hema Manjunath1,
- Asha Acharya1,
- Benjamin T. Jones1,
- He Zhang3,4,
- Beibei Chen3,4,
- Harini Ramalingam1,
- Robert E. Hammer5,
- Yang Xie3,4,6,
- James A. Richardson1,7,
- Dinesh Rakheja6,7,8,9,
- Thomas J. Carroll1,6,10,11 and
- Joshua T. Mendell1,6,11,12
- 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 3Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 4Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 5Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 6Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 7Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 8Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 9Division of Pathology and Laboratory Medicine, Children's Health, Dallas, Texas 75235, USA;
- 10Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 11Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 12Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Corresponding author: joshua.mendell{at}utsouthwestern.edu
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.315804.118.
- Received April 17, 2018.
- Accepted May 23, 2018.
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