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Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

Oncogene volume 21, pages 2948–2960 (2002)Cite this article

Abstract

The Wilms' tumour suppressor gene, WT1, encodes multiple nuclear protein isoforms, all containing four C-terminal zinc finger motifs. WT1 proteins can both activate and repress putative target genes in vitro, although the in vivo relevance of these putative target genes is often unverified. WT1 mutations can result in Wilms' tumour and the Denys-Drash Syndrome (DDS) of infantile nephropathy, XY pseudohermaphroditism and predisposition to Wilms' tumour. We have established stable transfectants of the mouse mesonephric cell line, M15, which express WT1 harbouring a common DDS point mutation (R394W). A comparison of the expression profiles of M15 and transfectant C2A was performed using Nylon-based arrays. Very few genes showed differential expression. However Wnt-4, a member of the Wnt gene family of secreted glycoproteins, was downregulated in C2A and other similar clones. Doxycycline induction of WT1-A or WT1-D expression in HEK293 stable transfectants also elicited an elevation in Wnt4 expression. Wnt4 is critical for the mesenchyme-to-epithelial transition during kidney development, making it an attractive putative WT1 target. We have mapped human Wnt-4 gene to chromosome 1p35-36, a region of frequent LOH in WT, have characterized the genomic structure of the human Wnt-4 gene and isolated 9 kb of immediate promoter. While several potential WT1 binding sites exist within this promoter, reporter analysis does not strongly support the direct regulation of Wnt4 by WT1. We propose that Wnt-4 regulation by WT1 occurs at a more distant promoter or enhancer site, or is indirect.

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Acknowledgements

We thank Veronica van Heyningen for provision of the M15 cells, David Porteous for molecular biological advice, Jeff Christianssen for technical support and Clontech for provision of the mouse Atlas arrays. E Szilagi was supported by a UNIMAS academic staff training program scholarship. MH Little is a Senior Research Fellow with the Sylvia and Charles Viertel Foundation. We thank all of the researchers who contributed cDNA clones (http:// www.cmcb.uq.edu.au/pubs/array.html). This work was supported by the National Health and Medical Research Council of Australia.

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Author notes

  1. Edmund U-H Sim

    Present address: Faculty of Resource Science and Technology, University Malaysia Sarawak (UNIMAS), 94300 Kota Samarahan, Sarawak, Malaysia

  2. Edmund U-H Sim and Aaron Smith: EU-H Sim and A Smith contributed equally to this work

Authors and Affiliations

  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, 4072, QLD, Australia

    Edmund U-H Sim, Aaron Smith, Elida Szilagi, Fiona Rae, Megan H Lindsay & Melissa H Little

  2. Department of Biochemistry, The University of Queensland, St Lucia, Brisbane, 4072, QLD, Australia

    Edmund U-H Sim, Elida Szilagi & Megan H Lindsay

  3. The Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, 3052, Australia

    Panos Ioannou

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Correspondence to Melissa H Little.

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Sim, EH., Smith, A., Szilagi, E. et al. Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1. Oncogene 21, 2948–2960 (2002). https://doi.org/10.1038/sj.onc.1205373

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