title: 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.
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;
authors.forename: Achia
authors.initials: A
authors.lastname: Urbach
authors.forename: Alena
authors.initials: A
authors.lastname: Yermalovich
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Spina
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: Rachel
authors.initials: R
authors.lastname: Shukrun
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Charlton
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.forename: William
authors.initials: W
authors.lastname: Mifsud
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007668:Kidney / Q000196:embryology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D009396:Wilms Tumor / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C516326:LIN28B protein, human; C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse
keywords: Lin28; Wilms tumor; kidney development
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