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Identification of novel Wilms' tumor suppressor gene target genes implicated in kidney development

  1. Author:
    Kim, H. S.
    Kim, M. S.
    Hancock, A. L.
    Harper, J. C. P.
    Park, J. Y.
    Poy, G.
    Perantoni, A. O.
    Cam, M.
    Malik, K.
    Lee, S. B.

  2. Author Address

    NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. NCI, Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. Univ Bristol, Canc & Leukaemia Childhood Sargent Unit, Dept Cellular & Mol Med, Bristol BS8 1TD, Avon, England.;Lee, SB, NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,9D11, Bethesda, MD 20892 USA.;seanL@intra.niddk.nih.gov
    1. Year: 2007
    2. Date: Jun
  2. Journal: Journal of Biological Chemistry
    1. 282
    2. 22
    3. Pages: 16278-16287
  4. Type of Article: Article
  5. ISSN: 0021-9258
  1. Abstract:

    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.

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External Sources

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  2. DOI: 10.1074/jbc.M700215200
  3. View record in Web of Science®
  4. WOS: 000246794300035

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