Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Author:

Berry Rachel L.1,Ozdemir Derya12,Aronow Bruce3,Lindström Nils O.12,Dudnakova Tatiana1,Thornburn Anna1,Perry Paul1,Baldock Richard1,Armit Chris1,Joshi Anagha2,Jeanpierre Cécile45,Shan Jingdong6,Vainio Seppo6,Baily James7,Brownstein David7,Davies Jamie8,Hastie Nicholas D.1,Hohenstein Peter12

Affiliation:

1. MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom

2. The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, United Kingdom

3. Department of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

4. INSERM, UMR 1163, Laboratory of inherited kidney diseases, 75015 Paris, France

5. Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France

6. Biocenter Oulu, Aapistie 5A, 90014, University of Oulu, P.O. Box 5000, Oulu, Finland

7. Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, United Kingdom

8. Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, United Kingdom

Abstract

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 to human tumour material of WT1-mutant and WT1 wild-type datasets identifies 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.

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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