Identification of novel radiation-induced p53-dependent transcripts extensively regulated during mouse brain development.

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.

Unraveling the fundamental molecular mechanisms of morphological and cognitive defects in the irradiated brain.

Prenatal radiation exposure may have serious consequences for normal brain development. Results of epidemiological studies clearly pointed towards an increased risk of mental retardation in children of the surviving women of the Hiroshima/Nagasaki atomic bombing when in utero exposure had occurred between weeks 8 and 15 of pregnancy or, at a lower extend between weeks 15 and 25. The high sensitivity of the developing brain, in comparison to the adult brain is related to its higher number of non-differentiated, dividing neural precursor cells. Exposure of the developing brain to ionizing radiation can lead to three main outcomes in the developing brain, depending on the radiation dose and the elapsed period after irradiation. A first event occurs early after irradiation and triggers disturbances in cell proliferation, migration, differentiation, and cell death. A second event involves the generation of morphological abnormalities in the developing brain, if the radiation dose is sufficient. A third event involves cognitive dysfunctions that are a direct consequence from a disturbance in regional brain formation. The latter results from exposure to low doses and is usually only observed in the later period of development. In order to understand the mechanisms of radiation-induced cognitive dysfunctions, it is important to track back the underlying changes in specific molecular pathways. In this review, we present the possible relationships within and between molecular pathways potentially involved in cognitive dysfunctions induced by ionizing radiation in the developing brain.