GSE63418
RNA sequencing data from beta-catenin activated, E2-2 wildtype and beta-catenin activated, E2-2 deleted cultured fetal mouse kidneys.
Oncogenic stabilizing mutations in the beta-catenin gene CTNNB1 are common in one class of human Wilms tumors. To model these tumors, we crossed mice carrying an inducible Cre recombinase (Rosa26-CreERT2) with a conditional gain-of-function beta-catenin allele (Ctnnb1Ex3flox). We obtained kidneys at embryonic day 13.5 and placed them in organ culture with tamoxifen. Multiple small tumors formed in the Ctnnb1?Ex3 kidneys while the control kidneys developed normally. Immunostaining for Sall1, a marker of condensing metanephric mesenchyme, indicated that the tumors arise from this tissue compartment, analogous to the origin of human Wilms tumors. Expression profiling identified a set of induced genes overlapping with those up-regulated in human Wilms tumors with CTNNB1 mutations, including genes encoding feedback inhibitors of Wnt/beta-catenin signaling, the epithelial-mesenchymal transition (EMT) inducers, and the transcription factor E2-2 (ITF2/TCF4). A conditional deletion of E2-2 showed that this gene is important for growth of the nephroblastomas, in part via promoting an epithelial to mesenchymal transition downstream of beta-catenin. Given these cross-species validations, and genetic proof of the oncogenic function of a key downstream target gene, we expect that this rapid and efficient organ culture model will be useful for further studies to dissect and inhibit oncogenic Wnt/beta-catenin signaling. Overall design: The expression of 4 beta-catenin activated, E2-2 wildtype cultured fetal mouse kidneys was compared with 3 beta-catenin activated, E2-2 deleted cultured fetal mouse kidneys.