Neurons break and repair their DNA during brain development

Neurons can experience and repair DNA breaks during healthy brain development, particularly as they migrate through tightly packed regions of the developing brain.

Researchers from the Kyoto University's Institute for Integrated Cell-Material Sciences in Japan have found that cerebellar granule neurons experience DNA double-strand breaks during developmental migration. These newborn neurons later integrate into functional neural circuits once they reach their target layers in the developing brain. The mechanical stress of moving through narrow interstitial spaces contributes to the formation of these breaks. However, the neurons generally survive this process and do not undergo cell death.

'The developing brain appears to have evolved to tolerate and repair the neuronal damage efficiently,' said Professor Mineko Kengaku, senior author of the study published in Nature. 'But understanding the limits of that tolerance – and what happens when repair is incomplete – brings us closer to understanding a range of neurological conditions.'

In collaboration with international researchers, the team modelled the journey of newborn neurons in vitro. By guiding neurons through microchannels that mimic the confined spaces of developing brain tissues, they used fluorescent markers to track the DNA damage in real time. They found that most double-strand breaks were repaired within 24 hours, with no detectable long-term effects on neuronal function in the experimental systems used. Genome analyses indicated that the double-strand breaks tended to occur in transcriptionally inactive regions of the genome, potentially limiting their impact on gene expression.

The double-strand breaks were linked to the activity of an enzyme called topoisomerase IIβ. Under mechanical stress, this enzyme can generate transient DNA breaks as part of its normal function in managing DNA topology, which are then repaired primarily via the non-homologous end joining (NHEJ) pathway.

To investigate the consequences of impaired repair, the team generated mice lacking a key NHEJ enzyme, DNA ligase IV, specifically in cerebellar granule neurons. While the animals developed normally, they later showed progressive balance and coordination deficits, resembling features seen in human genome instability syndromes. This suggests that accumulated DNA damage during normal brain development may contribute to disease risk if not properly repaired.

These findings prompt further research into whether these developmental DNA breaks contribute to neuronal diversity, as well as neurodevelopmental and neurodegenerative diseases. 

'It shifts how we think about the neuronal genome,' said Professor Kengaku. 'All neurons originate from the same DNA, but DNA damage and repair can introduce small genetic differences between individual neurons through a small mechanical journey. Some of that history may be written into the genome itself.'