Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Authors

  • Mirella Tanori,

    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
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  • Emanuela Pasquali,

    1. Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy
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  • Simona Leonardi,

    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
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  • Arianna Casciati,

    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
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  • Paola Giardullo,

    1. Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy
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  • Ilaria De Stefano,

    1. Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy
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  • Mariateresa Mancuso,

    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
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  • Anna Saran,

    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
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  • Simonetta Pazzaglia

    Corresponding author
    1. Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
    • Correspondence: Simonetta Pazzaglia, Ph.D., Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, 00123 Rome, Italy. Telephone: +39-06-3048–6535; Fax +39-06-3048–3644; e-mail: simonetta.pazzaglia@enea.it; or Anna Saran, Ph.D., Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, 00123 Rome, Italy. Telephone: +39-06-3048–4304; Fax: +39-06-3048–3644; e-mail: anna.saran@enea.it

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  • Author contributions: M.T. and E.P.: collection and/or assembly of data and data analysis and interpretation; S.L., A.C., P.G., and I.D.S.: collection and/or assembly of data; M.M.: data analysis and interpretation; A.S.: data analysis and interpretation, financial support, and manuscript writing; S.P.: conception and design, data analysis and interpretation, financial support, and manuscript writing. All authors read and approved the final manuscript. M.T. and E.P. contributed equally to this article.

Abstract

Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1+/−) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1+/− mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate-restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors. Stem Cells 2013;31:2506–2516

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