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A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes

Item Type:Article
Title:A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes
Creators Name:Ratelade, J. and Arrondel, C. and Hamard, G. and Garbay, S. and Harvey, S. and Biebuyck, N. and Schulz, H. and Hastie, N. and Pontoglio, M. and Gubler, M.C. and Antignac, C. and Heidet, L.
Abstract:The Wilms tumor-suppressor gene WT1, a key player in renal development, also has a crucial role in maintenance of the glomerulus in the mature kidney. However, molecular pathways orchestrated by WT1 in podocytes, where it is highly expressed, remain unknown. Their defects are thought to modify the cross-talk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS) a nephropathy associated with WT1 mutations. To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli and identified excellent candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Scel, encoding sciellin, a protein of the cornified envelope in the skin, and Sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild-type podocytes and to be strongly down-regulated in mutants. Co-expression of Wt1, Scel and Sulf1 was also found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. By ChIP we show that Scel and Sulf1 are direct WT1 targets. Cyp26a1, encoding an enzyme involved in the degradation of retinoic acid, is shown to be up-regulated in mutant podocytes. Cyp26a1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. These results provide novel clues in our understanding of normal glomerular function and early events involved in glomerulosclerosis.
Keywords:Alleles, Cell Line, Cytochrome P-450 Enzyme System, Denys-Drash Syndrome, Animal Disease Models, Gene Expression Profiling, Gene Expression Regulation, Heterozygote, Kidney Glomerulus, Mesonephros, Mutation, Podocytes, Protein Binding, Protein Transport, RNA Transport, Nucleic Acid Regulatory Sequences, Sulfotransferases, Genetic Transcription, WT1 Proteins, Animals, Mice
Source:Human Molecular Genetics
Publisher:Oxford University Press
Page Range:1-15
Date:1 January 2010
Official Publication:https://doi.org/10.1093/hmg/ddp462
PubMed:View item in PubMed

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