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The brain: a careful balance between stability and genetic variability

An IRCM (CEA-Jacob) team took a look at how neural stem and progenitor cells (which develop into neurons and other specialized cells in the brain) respond to acute and chronic genotoxic stress. The researchers showed that these cells are better at maintaining chromosome stability than their non-neural counterparts, and more capable of adapting to chronic stress. The work, published in DNA Repair, deciphers the mechanisms involved in maintaining genome integrity, a vitally important element of brain development.

Published on 20 July 2020

​Neural stem and progenitor cells (NSPCs) give rise to most of the brain's specialized cells, such as neurons, astrocytes and oligodendrocytes. A number of sometimes-severe nervous system diseases may result from damage to NSPCs during development. Such damage can result from genotoxic stress brought about by exposure to chemical agents or ionizing radiation, for example.

The Laboratory of Radiopathology of the mixed research unit Genetic Stability, Stem Cells and Radiation carried out an in vitro study to explore the response of NSPCs to acute (gamma radiation) and chronic (tritiated thymidine (³H-T) incorporated into DNA) genotoxic stress.

Using a murine model, the team showed that NSPCs maintain genomic integrity much more efficiently than do embryonic fibroblasts, which were used as experimental controls. The researchers reported that NSPCs showed better capacities for repairing DNA and activating apoptosis (also called programmed cell death), both contributing to improved maintenance of genomic integrity.

They also showed that NSPCs were able to adapt to chronic genotoxic stress. Indeed, ³H-T incorporation led to increasing chromosome instability over time in the mouse embryonic fibroblasts, but decreasing instability over time in the NSPCs. The adaptive response of these latter depended on the protein XLF, which is involved in non-homologous end-joining (NHEJ) DNA repair.

The stability of the NSPC genome appears of course essential for brain development and homeostasis. However, recent data suggest that genetic rearrangement does occur in NSPCs, enabling the generation of neurons with different functions in a manner similar to immune cells, where genetic rearrangement contributes to their diversity. 

The properties of NSPCs brought to light by this study could allow them to preserve genome integrity while also generating differentiated cells presenting a certain degree of genetic diversity.

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