p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis
Mbouombouo Mfossa, A. C.; Verslegers, M.; Verreet, T.; Fida, H. B.; Mysara, M.; van IJcken, W.; De Vos, W. H.; Moons, L.; Baatout, S.; Benotmane, M. A.; Huylebroeck, D.; Quintens, R.
Show abstract
p53 regulates the cellular DNA damage response (DDR). Hyperactivation of p53 during embryonic development, however, can lead to a range of developmental defects including microcephaly. Here, we induce microcephaly by acute irradiation of mouse fetuses at the onset of neurogenesis. Besides a classical DDR culminating in massive apoptosis, we observe ectopic neurons in the subventricular zone in the brains of irradiated mice, indicative of premature neuronal differentiation. A transcriptomic study indicates that p53 activates both DDR genes and differentiation-associated genes. In line with this, mice with a targeted inactivation of Trp53 in the dorsal forebrain, do not show this ectopic phenotype and partially restore brain size after irradiation. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process resembling the radiation-induced proneural-mesenchymal transition in glioma and glioma stem-like cells. Our results demonstrate a critical role for p53 beyond the DDR as a regulator of neural progenitor cell fate in response to DNA damage.
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