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TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma

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Abstract

The TCF4 gene encodes for the basic helix–loop–helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development.

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Acknowledgements

We thank Margarethe Gregersen, Michael Schmidt, and Anne Reichstein for excellent technical support. This study was supported by the German Cancer Aid, the Wilhelm Sander-Stiftung, the Kind-Philipp-Stiftung, the Burkhard Meyer Stiftung, and the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg.

Author information

Author notes

  1. Malte Hellwig and Marlen C. Lauffer contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Malte Hellwig, Michael Bockmayr, Dörthe Holdhof, Judith Niesen, Melanie Schoof & Ulrich Schüller

  2. Research Institute Children‘s Cancer Center Hamburg, Martinistrasse 52, N63 (HPI), 20251, Hamburg, Germany

    Malte Hellwig, Michael Bockmayr, Michael Spohn, Dörthe Holdhof, Judith Niesen, Melanie Schoof & Ulrich Schüller

  3. Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany

    Marlen C. Lauffer, Daniel J. Merk, Luke Harrison, Julia Ahlfeld, Annabel Kitowski, Julia E. Neumann, Jasmin Ohli & Ulrich Schüller

  4. Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands

    Marlen C. Lauffer

  5. Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Michael Bockmayr

  6. Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Michael Spohn

  7. Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany

    Daniel J. Merk

  8. Research Unit Neurobiology of Diabetes, Helmholtz Center Munich, Neuherberg, Germany

    Luke Harrison

  9. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Julia E. Neumann & Ulrich Schüller

  10. Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany

    Marcel Kool

  11. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Marcel Kool

  12. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany

    Cornelia Kraus & Christiane Zweier

  13. Department of Experimental Medical Science, Lund University, Lund, Sweden

    Dan Holmberg

Authors
  1. Malte Hellwig
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  2. Marlen C. Lauffer
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  3. Michael Bockmayr
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  4. Michael Spohn
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  5. Daniel J. Merk
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  6. Luke Harrison
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  7. Julia Ahlfeld
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  8. Annabel Kitowski
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  9. Julia E. Neumann
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  10. Jasmin Ohli
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  11. Dörthe Holdhof
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  12. Judith Niesen
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  13. Melanie Schoof
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  14. Marcel Kool
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  15. Cornelia Kraus
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  16. Christiane Zweier
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  17. Dan Holmberg
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  18. Ulrich Schüller
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Corresponding author

Correspondence to Ulrich Schüller.

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Hellwig, M., Lauffer, M.C., Bockmayr, M. et al. TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma. Acta Neuropathol 137, 657–673 (2019). https://doi.org/10.1007/s00401-019-01982-5

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  • DOI: https://doi.org/10.1007/s00401-019-01982-5

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