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Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation

Oncogene volume 32, pages 2304–2314 (2013)Cite this article

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A Corrigendum to this article was published on 16 July 2015

Abstract

Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax−/− mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax+/+ and Bax−/− medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.

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Acknowledgements

We thank James Olson, Fred Hutchinson Cancer Research Center for generously sharing ND2:SmoA1 mice; and Mervi Eeva, Jackie Kylander and Stephanie Cohen in the UNC Translational Pathology Laboratory (TPL) for expert technical assistance. The UNC TPL is supported, in part, by grants from the National Cancer Institute (3P30CA016086), National Institute of Environmental Health Sciences (3P30ES010126), Department of Defense (W81XWH-09-2-0042), and the UNC University Cancer Research Fund (UCRF). CRM is supported in part by a Clinical Investigator award from the Damon Runyon Cancer Research Foundation (CI-45-09). TRG is supported by a Scholar Award from the St Baldrick’s Foundation. Major portions of this work were supported by the Morgan Adams Foundation and the Matthew Larson Brain Tumor Foundation.

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Author notes

  1. I Garcia and A J Crowther: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    I Garcia, A J Crowther, C Ryan Miller & T R Gershon

  2. Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC, USA

    V Gama & M Deshmukh

  3. Department of Pathology and Laboratory Medicine, Division of Neuropathology, Translational Pathology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    C Ryan Miller

  4. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    C Ryan Miller, M Deshmukh & T R Gershon

  5. Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    C Ryan Miller, M Deshmukh & T R Gershon

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  1. I Garcia
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Correspondence to T R Gershon.

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Garcia, I., Crowther, A., Gama, V. et al. Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation. Oncogene 32, 2304–2314 (2013). https://doi.org/10.1038/onc.2012.248

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