Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

Abstract

Wilms tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations lead to WT, and reinforce the idea that the perturbation of the microRNA and IGF signalling pathways are important contributing factors in the aetiology of WT.