Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1-mutant mice

• Published in: Disease models & mechanisms Vol. 8; no. 8; pp. 903 - 917
• Main Authors: Berry, Rachel L, Ozdemir, Derya D, Aronow, Bruce, Lindström, Nils O, Dudnakova, Tatiana, Thornburn, Anna, Perry, Paul, Baldock, Richard, Armit, Chris, Joshi, Anagha, Jeanpierre, Cécile, Shan, Jingdong, Vainio, Seppo, Baily, James, Brownstein, David, Davies, Jamie, Hastie, Nicholas D, Hohenstein, Peter
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.08.2015; The Company of Biologists
• Subjects: Animals; Biomarkers - metabolism; Cell Lineage; Gene expression; Gene Expression Regulation, Neoplastic; Genome; Genomes; Integrases - metabolism; Kidney cancer; Kidney development; Kidneys; Mice, Inbred C57BL; Mice, Mutant Strains; Mouse model; Mutation; Neoplasm Staging; Nephrons - growth & development; Nephrons - metabolism; Nephrons - pathology; Oligonucleotide Array Sequence Analysis; Phenotype; Time-Lapse Imaging; Tumors; Wilms Tumor - genetics; Wilms Tumor - pathology; Wilms’ tumour; WT1; WT1 Proteins - genetics; WT1 Proteins - metabolism; Mouse model; WT1; Wilms’ tumour; Kidney development
• ISSN: 1754-8403; 1754-8411; 1754-8411; 1754-8403
• DOI: 10.1242/dmm.018523

Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin.