Characterization of irradiation-induced effects on murine cerebral cortex development

In this thesis, we aimed at elucidating some of the short-term changes in the irradiated embryonic neocortex that might be responsible for the microcephaly, as well as aberrant behavior, that was observed in previous experiments. Hereto, we focused on the dynamics of DNA damage and cell proliferation mechanisms, using Mus musculus as a model organism. We irradiated mice at E11, a time point which approximately corresponds to the 8th week of human pregnancy. We showed excessive DNA damage, with a dose-dependent occurrence of DNA double strand breaks (DSBs) in the irradiated developing murine cerebral cortex at 1 and 2 h after irradiation. This response was attenuated at 6 h post irradiation (PI) and completely absent at later time points. Until 2 h PI, 1.0 Gy irradiation caused a reduction in mitotic activity. Together with a reduced BrdU-PH3 doublestaining, which was confirmed with BrdU-pulse labeling experiments, these data provide evidence for a radiation-induced G2/M cell cycle arrest. At later time points, apoptosis was found mainly in the upper layers of the neocortex, without an apparent difference in cells exiting the cell cycle.