| During embryonic development, cell genesis is accompanied by the elimination of surplus cells by a mechanism termed Programmed Cell Death (PCD). PCD in the brain is regulated by survival signals, including limited growth factor availability and synaptic activity. Another factor that plays a critical, but imprecisely defined role in neuronal survival during cortical neurogenesis is DNA repair. DNA repair limits PCD and promotes cell survival. Repair of DNA Double Strand Breaks (DSB) by Non Homologous End Joining (NHEJ) utilizes Ku70/80, DNA-PKcs, DNA Lig-IV and XRCC4. We examined cortical development in mice deficient for the DNA end joining protein, Ku70. Mice lacking Ku70 exhibit higher levels of cortical PCD during embryonic and early neonatal development as well as increased vulnerability to apoptosis. Enhanced cell death in Ku70-deficient mice cell death, reduced brain size. Two groups of dying cells were evident: a GLAST+ neural progenitor population in the sub ventricular and ventricular zones, and a doublecortin+ immature neuron population in the intermediate zone, the latter exhibiting strong staining for oxidative DNA damage. Antioxidants and lower oxygen tension reduced the high levels of neuronal death in primary cortical cultures derived from Ku70-/- mice, but not the low levels of cell death in wildtype cortical cultures. Results indicate migrating cortical neurons undergo oxidative DNA damage, which is normally repaired by non-homologous end joining. Failure to repair oxidative damage triggers a form of apoptosis involving caspase-3 activation. |
