WT1 expression induces features of renal epithelial differentiation in mesenchymal fibroblasts

The WT1 tumor suppressor gene, implicated in hereditofamilial and sporadic Wilms' tumor, is required for normal renal development and is up-regulated during the mesenchymal-epithelial transition. NIH3T3 fibroblasts overexpres sing WT1 were less proliferative, larger in size and more firmly attached t o tissue culture plastic, suggesting an alteration of their state of differ entiation. These cells were studied in vivo by subcutaneous injection into nude mice, The resulting tumors exhibited epithelioid histopathology and fo rmed desmosome-like structures. Molecular analyses of these WT1 expressing fibroblasts grown in culture and in nude mice revealed significant alterati ons in the expression of many kidney epithelial markers. These studies indi cate that WT1 expression can initiate features of a program of epithelial d ifferentiation consistent with a prominent role for WT1 in the mesenchymal epithelial transition that occurs during renal development. Through this wo rk we identified a number of novel target genes for the WT1 transcription f actor, including uvomorulin, integrin alpha 8 and perlecan, and suggest tha t WT1 may activate the IGF-II gene, also implicated in the development of W ilms' tumor.