• Open Access

Lack of a p21waf1/cip-Dependent G1/S Checkpoint in Neural Stem and Progenitor Cells After DNA Damage In Vivo§

Authors

  • Telma Roque,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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    • Contributed equally to this article.

  • Céline Haton,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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    • Contributed equally to this article.

  • Olivier Etienne,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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    • Contributed equally to this article.

  • Alexandra Chicheportiche,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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    • Author contributions: T.R., C.H., and O.E.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; A.C., L.R., L.M., and M.-A.M.: collection and/or assembly of data; F.D.B.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Laure Rousseau,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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  • Ludovic Martin,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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  • Marc-André Mouthon,

    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
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  • François D. Boussin

    Corresponding author
    1. CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Univ Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Univ Paris-Sud, UMR 967, Fontenay-aux-Roses, France
    • 18, route du panorama, 92265 Fontenay-aux-Roses, France
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    • Author contributions: T.R., C.H., and O.E.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; A.C., L.R., L.M., and M.-A.M.: collection and/or assembly of data; F.D.B.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

    • Telephone: +33-1-46-54-97-91; Fax: +31-1-46-54-91-38


  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS December 12, 2011.

  • Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms

Abstract

The cyclin-dependent kinase inhibitor p21waf1/cip mediates the p53-dependent G1/S checkpoint, which is generally considered to be a critical requirement to maintain genomic stability after DNA damage. We used staggered 5-ethynyl-2′deoxyuridine/5-bromo-2′-deoxyuridine double-labeling in vivo to investigate the cell cycle progression and the role of p21waf1/cip in the DNA damage response of neural stem and progenitor cells (NSPCs) after exposure of the developing mouse cortex to ionizing radiation. We observed a radiation-induced p21-dependent apoptotic response in migrating postmitotic cortical cells. However, neural stem and progenitor cells (NSPCs) did not initiate a p21waf1/cip1-dependent G1/S block and continued to enter S-phase at a similar rate to the non-irradiated controls. The G1/S checkpoint is not involved in the mechanisms underlying the faithful transmission of the NSPC genome and/or the elimination of critically damaged cells. These processes typically involve intra-S and G2/M checkpoints that are rapidly activated after irradiation. p21 is normally repressed in neural cells during brain development except at the G1 to G0 transition. Lack of activation of a G1/S checkpoint and apoptosis of postmitotic migrating cells after DNA damage appear to depend on the expression of p21 in neural cells, since substantial cell-to-cell variations are found in the irradiated cortex. This suggests that repression of p21 during brain development prevents the induction of the G1/S checkpoint after DNA damage. STEM CELLS 2012;30:537–547

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