Tumour suppressor WT1 and its interacting protein RNA helicase DDX5 regulate the microRNA let7/Igf1r axis in the kidney mesenchyme

Abstract

Germline mutations in tumour suppressor, Wilms Tumour 1 (WT1) as well as somatic and germline mutations in microRNA processing genes (MIRPG) have been identified in Wilms Tumours (WT), where upregulation of IGF2 through genetic and/or epigenetic mechanisms is commonly seen. Whether these different epigenetic and genetic causes converge on common targets is still unclear. WT1 is also involved in RNA binding and regulates the stability of these developmental mRNAs. We now show that WT1 interacts with microRNA let-7 and proteins involved in microRNA processing wherein DDX5 is found to be an important regulator. WT1 absence results in decreased microRNA levels in cell lines and kidney mesenchyme, which is further downregulated in a WT1 and DDX5 double knockdown, ultimately modulating Igf1r expression. These findings suggest a plausible mechanism by which WT1 mutations lead to WT, and converge on microRNA pathway and IGF signalling pathway, which are important contributing factors in the aetiology of WT.