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J. Biol. Chem., Vol. 282, Issue 22, 16278-16287, June 1, 2007

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Identification of Novel Wilms' Tumor Suppressor Gene Target Genes Implicated in Kidney Development^*

Ho-Shik Kim¹², Myoung Shin Kim¹, Anne L. Hancock, James C. P. Harper, Jik Young Park, George Poy^¶, Alan O. Perantoni^||, Margaret Cam^¶, Karim Malik, and Sean Bong Lee³

From the Genetics of Development and Disease Branch, ^¶Microarray Core Facility, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ^||Laboratory of Comparative Carcinogenesis, NCI-Frederick, Frederick, Maryland 21702, and Cancer and Leukaemia in Childhood Sargent Unit, Department of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom

The Wilms' tumor suppressor gene (WT1) encodes a zinc finger transcription factor that is vital during development of several organs including metanephric kidneys. Despite the critical regulatory role of WT1, the pathways and mechanisms by which WT1 orchestrates development remain elusive. To identify WT1 target genes, we performed a genome-wide expression profiling analysis in cells expressing inducible WT1. We identified a number of direct WT1 target genes, including the epidermal growth factor (EGF)-family ligands epiregulin and HB-EGF, the chemokine CX3CL1, and the transcription factors SLUG and JUNB. The target genes were validated using quantitative reverse transcriptase-polymerase chain reaction, small interfering RNA knockdowns, chromatin immunoprecipitation, and luciferase reporter analyses. Immunohistochemistry of fetal kidneys confirmed that a number of the WT1 target genes had overlapping expression patterns with the highly restricted spatiotemporal expression of WT1. Finally, using an in vitro embryonic kidney culture assay, we found that the addition of recombinant epiregulin, amphiregulin, CX3CL1, and interleukin-11 significantly enhanced ureteric bud branching morphogenesis. Our genome-wide screen implicates WT1 in the transcriptional regulation of the EGF-family of growth factors as well as the CX3CL1 chemokine during nephrogenesis.

Received for publication, January 8, 2007 , and in revised form, April 2, 2007.

^* This research was supported in part by the Intramural Research Program of the NIDDK, National Institutes of Health (to S. B. L.), and by the Cancer and Leukaemia in Childhood-Sargent Trust (to K. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Tables S1–S3.

¹ These authors contributed equally to this study.

² Present address: Dept. of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.

³ To whom correspondence should be addressed: Genetics of Development and Disease Branch, 9000 Rockville Pike, Bldg. 10, 9D11, Bethesda, MD 20892. Tel.: 301-496-9739; Fax: 301-480-0638; E-mail: seanL{at}intra.niddk.nih.gov.

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