Cancer, Development and the Multifunctional Wilms Tumour Gene, WT1

Wilms tumour is a kidney cancer that is quite common in children during the first 5 years of life. It is clearly a remarkable example of cancer arising through the normal processes of development going wrong. In order to understand how the tumour develops with a view to better treatments, we have to understand the processes of normal kidney development and how these go awry on the route to tumorigenesis. We are studying a Wilms tumour predisposition gene, WT1, mutations in which result in Wilms tumour but may also lead to other life-threatening kidney diseases and abnormalities of the sexual organs. We have shown that this gene is vital for normal kidney, testis and ovary development and one of our major goals is to understand how WT1 controls differentiation of these tissues and why disease develops when the gene is mutated. We have shown that WT1 is necessary for cells to divide and to prevent differentiation in certain tissues such as blood vessels of the heart. We propose to dissect WT1s role in these processes and to test the idea that it may play a major role in stem cell maintenance, tissue repair and in adult cancer. We have also shown WT1 is a remarkable example of a single gene encoding multiple proteins that may differentially regulate gene expression both in the nucleus and in the cytoplasm. One of our major goals is to understand these functions and how they control normal development and disease. We are taking a multidisciplinary approach to our work and are trying to set-up novel systems in culture to test the function of WT1 and associated genes.

Mutations in the Wilms tumour suppressor gene, WT1, may lead not only to the eponymous childhood kidney cancer, but also to severe glomerular nephropathy and gonadal dysgenesis, including sex reversal. In order to understand the mechanisms underlying these conditions with a view to novel therapies, we must elucidate the roles of WT1 in normal genitourinary development and establish mouse models that mimic the human diseases as closely as possible. Our studies so far indicate that whereas WT1 is essential for terminal differentiation of the kidney nephron, consistent with its role as a tumour suppressor, in other tissues such as heart, great vessels and liver, WT1 appears to play the reverse role, i.e. maintaining vascular and other progenitors in an undifferentiated state. In these cases, we suggest it is necessary to shut off WT1 function for cells to terminally differentiate. Our findings provide a basis for the growing view that WT1 may act as an oncogene in some common adult cancers where it is highly expressed.||We aim to continue to dissect the roles of WT1 in normal kidney development. We are using a conditional WT1 model to dissect roles for WT1 in different stages of nephron development. We have strong data to support a model where in condensing mesenchyme WT1 directly activates WNT4, the essential signalling molecule in the epithelialization of the nephron. We are extending this with analyzing the downstream pathways of WNT4 in this process, and new models (in vitro and in vivo) to understand the role of beta-catenin mutations in Wilms tumors. We re hoping combined all this will help us to develop a mouse model for Wilms tumors. We are also testing the hypothesis that WT1 maintains progenitor cells in an undifferentiated state in the heart, liver and some specific neurons. Furthermore, we will use cellular and whole animal models to rigorously test the hypothesis that WT1 is an oncogene in adult cancers and to dissect the mechanisms and pathways involved. In this context a major development is the role we have identified for WT1 in regulating epithelial to mesenchymal transitions by direct regulation of Snail.||In order to understand the roles of WT1 in development and disease, we must understand its function at the biochemical and cellular levels. The WT1 gene encodes multiple protein isoforms, each including 4 C2H2 zinc fingers. There is a considerable body of evidence that WT1 acts as a transcription factor. However, work mainly from this group suggests that some WT1 isoforms regulate gene expression at the post-transcriptional level. We propose to use a variety of approaches to identify target genes and RNAs directly regulated by WT1 in the nucleus and cytoplasm and will dissect the function of different isoforms in post-transcriptional processes.||Parts of the programme on kidney development in particular can now be placed in a broader context as they have strong links with the EU FP6 programme, EUREGENE, and with the NIDDK Genitourinary Atlas programme, PI Duncan Davidson. With our EUREGENE colleagues, we will be exploring new approaches to studying genetic pathways underlying nephrogenesis and to model kidney anatomy in 3D with the help of OPT. The ultimate aim is to build a 4D genitourinary atlas and database which can be used to formulate new hypotheses and to facilitate translational research.