Lin28 sustains early renal progenitors and induces Wilms tumor

Achia Urbach, Alena Yermalovich, Jin Zhang, Catherine S. Spina, Hao Zhu, Antonio R. Perez-Atayde, Rachel Shukrun, Jocelyn Charlton, Neil Sebire, William Mifsud, Benjamin Dekel, Kathy Pritchard-Jones, George Q. Daley

Research output: Contribution to journalArticle

94 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)971-982
Number of pages12
JournalGenes and Development
Volume28
Issue number9
DOIs
StatePublished - May 1 2014

Keywords

  • Kidney development
  • Lin28
  • Wilms tumor

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Urbach, A., Yermalovich, A., Zhang, J., Spina, C. S., Zhu, H., Perez-Atayde, A. R., Shukrun, R., Charlton, J., Sebire, N., Mifsud, W., Dekel, B., Pritchard-Jones, K., & Daley, G. Q. (2014). Lin28 sustains early renal progenitors and induces Wilms tumor. Genes and Development, 28(9), 971-982. https://doi.org/10.1101/gad.237149.113