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WT1 regulates expression of pro and anti angiogenic isoform of VEGF

The Wilms tumour suppressor gene WT1 is mutated in Denys Drash Syndrome (DDS). DDS is characterised by childhood nephrotic syndrome, glomerulosclerosis, end‐stage renal failure and Wilms tumours. VEGF splicing is altered in DDS patients' kidneys (Schumacher et al 2007). The splice factor ASF/SF2 a known proto‐oncogene (Krainer et al), shuttles between the nucleus and cytoplasm promotes the splicing to the pro angiogenic isoform of VEGF (Nowak et al 2008). In DDS podocytes there is a 8.7+0.003 fold reduction in VEGFxxxb compared to wildtype. DDS podocytes stably transfected with a plasmid expressing wildtype WT1 restored the expression of VEGFxxxb to 0.73+0.08. In the DDS podocytes, ASF/SF2 was predominantly localized in the nucleus while the DDS podocytes transfected with wildtype WT1 had ASF/SF2 equally localized between the cytoplasm and nucleus similar to the wildtype podocytes. The localization of ASF/SF2 dependent on phosphorylation by kinases such as SR‐protein‐specific kinase 1 (SRPK1). Western blot and qPCR analysis of SRPK1 levels reveals a higher expression protein and mRNA transcripts in the DDS podocytes. The ''rescued' DDS podocytes had a reduction in both protein and mRNA level of SRPK1 similar to the wildtype podocytes. These findings suggest that the tumour suppressor WT1 regulates splicing through a novel mechanism by transcriptionally regulating a key kinase involved in the RNA machinery.