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Ionizing radiation induced transcriptional changes in the developing mouse brain

vrijdag, 15 december, 2006 - 16:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculteit: Science and Bio-engineering Sciences
D
0.03
Joris Verheyde
doctoraatsverdediging

The brain is the final result of a series of well timed consecutive waves of cellular proliferation, migration, and differentiation. Acute irradiation during pregnancy could selectively disturb these events to result in various forms of malformations. In this work we concentrated on the transcriptional alterations induced by ionising radiation in the mouse developing brain and its different cell-types. We analysed the modulated gene expression profile after 50 cGy X-ray exposure in embryonic mouse total brains at developmental stages E13, E15 and E18. A decreasing expression profile could be identified at later development, which suggests a reduction in radiosensitivity. Functional grouping of the modulated mRNA transcripts revealed that the main activated pathways in irradiated wild type embryos are involved in the induction of Trp53 dependent programmed cell death and intracellular signalling cascades. Trp53 null mutants showed a decreased expression profile for the Cyclins and Cdk's, involved in the G2 cell cycle phase. To determine possible regional differences we evaluated the radiation induced transcriptional response in three different regions of the telencepehalon. Further analysis showed that the strongest radiation induced effect was observed in the cerebral cortex. Since cell type dependent differences can be observed after radiation exposure, we evaluated the neural cell-type and differentiation-stage dependent radiation induced transcriptional and cellular responses. Detailed analysis of short-term cultured and irradiated neural cell types indicated that the expression of the Trp53inp1/Hipk2 and Ccng1/Mdm2 signalling pathways are activated in a cell-type dependent matter. Interestingly, long term cultured neurons show also an induction of apoptosis irradiation, but they were not characterized by an increased expression of Cdkn1a. To conclude, we demonstrate also that ionising radiation does not only influence cell survival, but induces also the impairment of neural differentiation may contribute to an incorrect formation of the neural network.