In vivo importance of homologous recombination DNA repair for mouse neural stem and progenitor cells

We characterized the in vivo importance of the homologous recombination factor RAD54 for the developing mouse brain cortex in normal conditions or after ionizing radiation exposure. Contrary to numerous homologous recombination genes, Rad54 disruption did not impact the cortical development without exogenous stress, but it dramatically

No interference of <i>Rad54</i> disruption with radiation response of G1 and postmitotic cells within 8 hPI.

<p><b>A</b> Scheme of the experimental design. <b>B and C</b> Number per bin of normally shaped (left) and pyknotic nuclei (right), from top to bottom, EdU(−)BrdU(+) (<b>B</b>) and EdU(−)BrdU(−) (<b>C</b>) nuclei 4 h (top) and 8 h (bottom) after a 1 Gy (orange), 2 Gy (black) or 0 Gy (green, control) radiation exposure. Mean values ± SEM were calculated from <i>WT</i> (closed squares) and <i>Rad54−/−</i> (open squares) embryos from at least three distinct litters for each genotype. Stars correspond to statistical analysis between <i>WT</i> and <i>Rad54−/−</i> curves.</p

<i>Rad54</i> disruption lengthens G2/M arrest and delayed S-phase progression in S and G2 irradiated NSPC.

<p><b>A</b> Scheme of the experimental design. Repeated BrdU injections were performed in order to insure perfect staining of all neural cells newly entering S phase during the 4 or 8 hours PI. <b>B and C</b> Number per bin of normally shaped (left) and pyknotic nuclei (right), from top to bottom, EdU(+)BrdU(−) (<b>B</b>) and EdU(+)BrdU(+) (<b>C</b>) nuclei 4 h (top) and 8 h (bottom) after a 1 Gy (orange), 2 Gy (black) or 0 Gy (green, control) radiation exposure. Mean values ± SEM were calculated from <i>WT</i> (closed squares) and <i>Rad54−/−</i> (open squares) embryos from at least three distinct litters for each genotype. Stars correspond to statistical analysis between <i>WT</i> and <i>Rad54−/−</i> curves.</p

Fanconi DNA repair pathway is required for survival and long-term maintenance of neural progenitors

Although brain development abnormalities and brain cancer predisposition have been reported in some Fanconi patients, the possible role of Fanconi DNA repair pathway during neurogenesis is unclear. We thus addressed the role of fanca and fancg, which are involved in the activation of Fanconi pathway, in neural stem and progenitor cells during brain development and adult neurogenesis. Fanca−/− and fancg−/− mice presented with microcephalies and a decreased neuronal production in developing cortex and adult brain. Apoptosis of embryonic neural progenitors, but not that of postmitotic neurons, was increased in the neocortex of fanca−/− and fancg−/− mice and was correlated with chromosomal instability. In adult Fanconi mice, we showed a reduced proliferation of neural progenitor cells related to apoptosis and accentuated neural stem cells exhaustion with ageing. In addition, embryonic and adult Fanconi neural stem cells showed a reduced capacity to self-renew in vitro. Our study demonstrates a critical role for Fanconi pathway in neural stem and progenitor cells during developmental and adult neurogenesis