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J Am Soc Nephrol. 2015 Sep;26(9):2118-28. doi: 10.1681/ASN.2014080819. Epub 2015 Jan 2.

Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms' Tumor 1 Target Genes in Podocyte Differentiation and Maintenance.

Author information

1
Departments of Molecular Genetics and.
2
Genome Analysis, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany;
3
Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany;
4
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; and.
5
Departments of Molecular Genetics and Faculty of Biology and Pharmacy, Friedrich Schiller University of Jena, Jena, Germany cenglert@fli-leibniz.de.

Abstract

The Wilms' tumor suppressor gene 1 (WT1) encodes a zinc finger transcription factor. Mutation of WT1 in humans leads to Wilms' tumor, a pediatric kidney tumor, or other kidney diseases, such as Denys-Drash and Frasier syndromes. We showed previously that inactivation of WT1 in podocytes of adult mice results in proteinuria, foot process effacement, and glomerulosclerosis. However, the WT1-dependent transcriptional network regulating podocyte development and maintenance in vivo remains unknown. Here, we performed chromatin immunoprecipitation followed by high-throughput sequencing with glomeruli from wild-type mice. Additionally, we performed a cDNA microarray screen on an inducible podocyte-specific WT1 knockout mouse model. By integration of cistromic and transcriptomic analyses, we identified the WT1 targetome in mature podocytes. To further analyze the function and targets of WT1 in podocyte maturation, we used an Nphs2-Cre model, in which WT1 is deleted during podocyte differentiation. These mice display anuria and kidney hemorrhage and die within 24 hours after birth. To address the evolutionary conservation of WT1 targets, we performed functional assays using zebrafish as a model and identified Nphs2, Mafb, and Magi2 as novel WT1 target genes required for podocyte development. Our data also show that both Mafb and Magi2 are required for normal development of the embryonic zebrafish kidney. Collectively, our work provides insights into the transcriptional networks controlled by WT1 and identifies novel WT1 target genes that mediate the function of WT1 in podocyte differentiation and maintenance.

KEYWORDS:

ESRD; chronic hemodialysis; economic analysis; epidemiology and outcomes; outcomes; vascular access

PMID:
25556170
PMCID:
PMC4552121
DOI:
10.1681/ASN.2014080819
[Indexed for MEDLINE]
Free PMC Article

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