Abstract
We characterized the in vivo importance of the homologous recombination factor RAD54 for the developing mouse brain cortex in normal conditions or after ionizing radiation exposure. Contrary to numerous homologous recombination genes, Rad54 disruption did not impact the cortical development without exogenous stress, but it dramatically enhanced the radiation sensitivity of neural stem and progenitor cells. This resulted in the death of all cells irradiated during S or G2, whereas the viability of cells irradiated in G1 or G0 was not affected by Rad54 disruption. Apoptosis occurred after long arrests at intra-S and G2/M checkpoints. This concerned every type of neural stem and progenitor cells, showing that the importance of Rad54 for radiation response was linked to the cell cycle phase at the time of irradiation and not to the differentiation state. In the developing brain, RAD54-dependent homologous recombination appeared absolutely required for the repair of damages induced by ionizing radiation during S and G2 phases, but not for the repair of endogenous damages in normal conditions. Altogether our data support the existence of RAD54-dependent and -independent homologous recombination pathways.
Highlights
During development of the mammalian brain, neural stem and progenitor cells (NSPC) proliferate, undergo differentiation and migrate in a precisely coordinated manner before they become mature cell types in the central nervous system
Setting up an efficient DNA damage response leading to the accurate repair or elimination of damaged cells is an important challenge for highly proliferative fetal stem cells, which are supposed to insure the fidelity of the transmission of their genomes to their progeny and supposed to preserve both self-renewal capacity and multipotency
Contrary to the inactivation of major homologous recombination (HR) factors, leading to early embryonic lethality [22,23], Rad54 disruption does not impair mouse viability [34] and we have shown here that it did not impact the cortical development in normal conditions
Summary
During development of the mammalian brain, neural stem and progenitor cells (NSPC) proliferate, undergo differentiation and migrate in a precisely coordinated manner before they become mature cell types in the central nervous system. Among the NSPC of the developing cortex, radial glia cells (RGC) functions as neural stem cells and generate neurons directly or indirectly via intermediate progenitors (IPC) [1,2]. Newborn IPC migrate to a more basal zone called the subventricular zone (SVZ) where they divide symmetrically to give a pair of IPC or a pair of neurons [4]. Newborn neurons migrate along the cytoplasm of RGC through the intermediate zone (IZ) to reach the cortical plate (CP), their final destination at the basal lamina [2,4,5]
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