Lack of a p21 waf1/cip ‐Dependent G1/S Checkpoint in Neural Stem and Progenitor Cells After DNA Damage In Vivo

• DOI: 10.1002/stem.1010
• Publication Date: 2011-12-12T19:52:35Z
• Authors: Telma Roque; Céline Haton; Olivier Etienne; Alexandra Chichep...; Laure Rousseau; Ludovic Martin; Marc‐André Mouthon; François D. Boussin
• Keywords: Cell Nucleus; Cyclin-Dependent Kinase Inhibitor p21; Mice, Knockout; 0301 basic medicine; Mice, 129 Strain; Apoptosis; Embryo, Mammalian; G1 Phase Cell Cycle Checkpoints; Genomic Instability; Statistics, Nonparametric; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Neural Stem Cells; Pregnancy; Lateral Ventricles; S Phase Cell Cycle Checkpoints; Animals; Female; Neuroglia; Original Research: Tissue-Specific Stem Cells; Cell Proliferation; DNA Damage

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.