title: Lack of a p21waf1/cip -dependent G1/S checkpoint in neural stem and progenitor cells after DNA damage in vivo.
abstract: The cyclin-dependent kinase inhibitor p21(waf1/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 p21(waf1/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 p21(waf1/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.
authors.affiliation: CEA, DSV IRCM SCSR, Laboratoire de Radiopathologie, UMR 967, Fontenay-aux-Roses, France.
authors.forename: Telma
authors.initials: T
authors.lastname: Roque
authors.forename: Céline
authors.initials: C
authors.lastname: Haton
authors.forename: Olivier
authors.initials: O
authors.lastname: Etienne
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chicheportiche
authors.forename: Laure
authors.initials: L
authors.lastname: Rousseau
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martin
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Mouthon
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000528:radiation effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000528:radiation effects*; D042822:Genomic Instability / Q000528:radiation effects; D020547:Lateral Ventricles / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D009457:Neuroglia / Q000502:physiology / Q000528:radiation effects; D011247:Pregnancy; D059807:S Phase Cell Cycle Checkpoints / Q000528:radiation effects; D018709:Statistics, Nonparametric
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21