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

Ryan W Hunter; Yangjian Liu; Hema Manjunath; Asha Acharya; Benjamin T Jones; He Zhang; Beibei Chen; Harini Ramalingam; Robert E Hammer; Yang Xie; James A Richardson; Dinesh Rakheja; Thomas J Carroll; Joshua T Mendell

doi:10.1101/gad.315804.118

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

Genes Dev. 2018 Jul 1;32(13-14):903-908. doi: 10.1101/gad.315804.118. Epub 2018 Jun 27.

Authors

Ryan W Hunter^{1

2}, Yangjian Liu¹, Hema Manjunath¹, Asha Acharya¹, Benjamin T Jones¹, He Zhang^{3

4}, Beibei Chen^{3

4}, Harini Ramalingam¹, Robert E Hammer⁵, Yang Xie^{3

4

6}, James A Richardson^{1

7}, Dinesh Rakheja^{6

7

8

9}, Thomas J Carroll^{1

6

10

11}, Joshua T Mendell^{1

6

11

12}

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
² Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
³ Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁴ Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁵ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁶ Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁷ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁹ Division of Pathology and Laboratory Medicine, Children's Health, Dallas, Texas 75235, USA.
¹⁰ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
¹¹ Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
¹² Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, 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: DIS3L2; Igf2; LIN28; Perlman syndrome; Wilms tumor; let-7; microRNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Disease Models, Animal
Exoribonucleases / genetics*
Fetal Macrosomia / genetics*
Humans
Insulin-Like Growth Factor II / genetics*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
MicroRNAs / genetics
Mutation
Nephrons / cytology
Nephrons / physiopathology
Stem Cells
Up-Regulation*
Wilms Tumor / genetics*

Substances

MicroRNAs
mirnlet7 microRNA, mouse
Insulin-Like Growth Factor II
Dis3l2 protein, mouse
Exoribonucleases

Supplementary concepts

Nephroblastomatosis, fetal ascites, macrosomia and Wilms tumor

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding