Lin28 sustains early renal progenitors and induces Wilms tumor.

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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Urbach A,Yermalovich A,Zhang J,Spina CS,Zhu H,Perez-Atayde AR,Shukrun R,Charlton J,Sebire N,Mifsud W,Dekel B,Pritchard-Jones K,Daley GQ

doi

10.1101/gad.237149.113

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

971-82

issue

9

eissn

0890-9369

issn

1549-5477

pii

gad.237149.113

journal_volume

28

pub_type

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