Nick Hastie Research Group (Affiliate)
Cancer, Development and Adult Tissue Maintenance
Section: Disease Mechanisms
Research in a Nutshell
The study of genes mutated in human disease can lead to insights into fundamental biological processes as well as disease mechanisms. One such gene is the Wilms' tumour 1 gene, WT1.
Mutations in this gene may lead to childhood kidney cancer, glomerulosclerosis of the kidney, gonadal dysgenesis, and in rare cases, diaphragmatic hernia and heart disease. We have shown that these conditions arise in the main through disturbances in the conversion between mesenchymal and epithelial states in these different tissues. In mice WT1 is essential for the development of these and some other tissues arising from the intermediate and lateral plate mesoderm. In the kidney we have shown WT1 is required for the mesenchyme to epithelial transition that produces epithelial nephrons. Conversely in the developing heart we have shown WT1 is required in the epicardium (a mesothelium) for the epithelial to mesenchyme transition that produces progenitors for coronary vasculature. To investigate whether these processes may continue postnatally we deleted WT1 in adult mice. Remarkably within 10 days the mice had severe kidney disease, extreme atrophy of the spleen and exocrine pancreas and, most surprisingly reduction in body fat and bone density. Following up this observation we showed WT1 uniquely identifies and regulates progenitors for visceral adipose tissue, excess of which is associated with risk of diabetes, heart disease and cancer. What's more, we showed the source of these progenitors is the mesothelial layer that lines visceral fat depots. This work received widespread coverage in the national and international media. As well as regulating development and tissue homeostasis WT1 is reactivated during tissue repair and this is a topic we are currently investigating.
With regard to the molecular mechanisms by which it exerts it effects WT1 contains 4 zinc fingers and can function as a transcription activator or repressor. We have shown WT1 achieves this by binding to specific co-activators or repressors and through a chromatin switching mechanism. However, over many years my lab has obtained evidence that WT1 also functions post-transcriptionally but we had not identified the endogenous target RNAs or mechanisms by which it acts. Now using a UV crosslinking approach, we have identified the global WT1 RNA interactome. We have found Wt1 interacts with secondary RNA structures in the 3' UTR end of developmental mRNAs. Knockdown of WT1 leads to downregulation of these target RNAs and we have proposed a model by which WT1-stabilised 3’ UTR fold over prevents access of microRNAs. We have also shown WT1 binds to secondary structures within miRNAs and regulates the levels of mature miRNAs. These findings, some under submission, concur well with recent studies showing mutation of RNA processing genes in a proportion of Wilms' tumour cases. My main programme is to dissect the molecular mechanisms by which WT1 regulates these and other posttranscriptional processes and to determine the relevance of these events in development, homeostasis, repair and disease.