The role of p53 in radiation-induced microcephaly in mice

The developing brain is highly sensitive to ionizing radiation (IR). Many studies indicated that exposure to moderate to high dose of IR during embryonic neurogenesis results in brain developmental defects such as microcephaly. A previous study conducted at the Radiobiology Unit of SCK•CEN has demonstrated that p53-mediated gene expression changes in these brains, shortly after radiation exposure, highly overlapped with those induced in the Magoh+/− mouse, a genetic mouse model of microcephaly, and in human neural progenitor cells infected with Zika virus. Our working hypothesis is that p53-modulated target gene transcription early after radiation exposure is responsible for the subsequent development of microcephaly. The main objectives of this study were (i) examining the potential role of p53 in the development of radiation-induced microcephaly (ii) dissecting the possible cellular and molecular mechanisms underlying this detrimental effect. To reach our objectives, Emx1cre/+Trp53fl/fl conditional knock-out (cKO) mice were X-irradiated at the onset of neurogenesis, embryonic day 11 (E11), and brain sizes were compared with Emx1+/+Trp53fl/fl (WT) mice. Furthermore, underlying cellular and molecular mechanisms were compared and analyzed by performing immunohistochemistry. Our results showed that radiation induces a widespread transient DNA-damage in the embryonic brain which was independent of Trp53 status. In WT mice, this was accompanied by an arrest of neural progenitor cell proliferation at the G2/M checkpoint of the cell cycle. Compared to irradiated WT mice, cell cycle arrest was attenuated at 2 h after irradiation in irradiated cKO mice whereas 6 h post-irradiation the cell cycle had completely resumed indicating a p53-dependent component of cell-cycle regulation. Furthermore, massive p53-dependent cell death following radiation was observed. Premature differentiation was evidenced by the p53-dependent reduction of the pool of neural progenitor cells in irradiated WT mice in comparison to cKO mice. In parallel, and exclusively in irradiated WT embryos, ectopic immature neurons in the apical zone of the cortex were observed. Furthermore, a p53 dependent reduction of the number of Qki5 (a protein known to repress epithelial cell adhesion) positive cells in the ventricular zone expressing cells were significantly reduced in irradiated WT mice. p53 plays a significant role in the development of DNA damaged-induced microcephaly, which is partly on account of its pro-apoptotic activity, its involvement in cell cycle arrest, premature neuronal differentiation which may involve an epithelial to mesenchymal transition (EMT) like mechanism. Hence our findings provide an interesting reference for future research to document the use of p53 pharmacological inhibitors to prevent the detrimental effect of IR