Lin28 sustains early renal progenitors and induces Wilms tumor
- Achia Urbach1,2,3,4,
- Alena Yermalovich1,2,3,4,
- Jin Zhang1,2,3,4,
- Catherine S. Spina1,2,3,4,
- Hao Zhu5,6,7,
- Antonio R. Perez-Atayde8,
- Rachel Shukrun9,10,
- Jocelyn Charlton11,
- Neil Sebire12,
- William Mifsud12,
- Benjamin Dekel9,10,
- Kathy Pritchard-Jones11 and
- George Q. Daley1,2,3,4,13
- 1Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children’s Hospital Boston, Boston, Massachusetts 02115, USA;
- 2Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
- 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 4Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;
- 5Children’s Research Institute,
- 6Department of Pediatrics,
- 7Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 8Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA;
- 9Pediatric Stem Cell Research Institute,
- 10Division of Pediatric Nephrology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv 52621, Israel;
- 11Institute of Child Health, University College London, London WC1H 0AJ, United Kingdom;
- 12Department of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children, London WC1N 3JH, United Kingdom
Abstract
Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.
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Footnotes
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↵13 Corresponding author
E-mail george.daley{at}childrens.harvard.edu
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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.237149.113.
- Received December 24, 2013.
- Accepted March 25, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
