Developing brain cells routinely repair severe DNA damage during migration

Newborn nerve cells must squeeze through crowded, narrow spaces-through dense tissue, past other cells, between fibers-to reach the areas where they form neural circuits in the brain cortex. 

In a new study published in Nature, researchers at Kyoto University's Institute for Integrated Cell-Material Sciences (WPI-iCeMS) and their collaborators report that this journey causes widespread DNA damage in neurons, resulting in double-strand breaks where both strands of the double helix are completely severed. While this is the most severe type of DNA damage-capable of causing mutations and cell death-the team surprisingly found that it is a normal, routine feature of brain cortex formation, and a healthy brain quickly repairs it before harm occurs. 

"The developing brain appears to have evolved to tolerate and repair the neuronal damage efficiently," says Professor Mineko Kengaku, of WPI-iCeMS, who led the study. "But understanding the limits of that tolerance-and what happens when repair is incomplete-brings us closer to understanding a range of neurological conditions."

The team mimicked the journey by guiding neurons through microchannels designed to replicate the narrow spaces in developing brain tissue. Fluorescent markers revealed DNA double-strand breaks forming as the cells passed through the channels, then disappearing after they had reached the other side. Most were repaired within 24 hours, with no lasting effects on function.

The researchers traced the DNA breaks to Topoisomerase IIβ, an enzyme that normally makes controlled cuts in DNA to release the torsional strain of everyday cellular activity. It's similar to snipping a twisted cable to untangle it and then splicing it back together. Under mechanical stress, the enzyme becomes stuck mid-process, leaving broken ends of DNA. A repair pathway-known as non-homologous end joining-stitches these broken ends back together.

This differs sharply from what happens in some cancer cells migrating through the same microchannels, where DNA damage occurs more randomly, impairing cellular function or even killing the cells. In neurons, this damage occurs mainly in non-critical regions of the genome rather than in active genes, so overall function is preserved.

To test what happens if this repair fails, the team engineered mice in which new neurons in the cerebellum lacked Ligase 4, a key repair enzyme. The animals developed normally, but they gradually showed mild, progressive balance difficulties from early adulthood-symptoms reminiscent of human genome instability syndromes that affect the cerebellum.

The findings raise new questions about whether these early breaks contribute to neuronal individuality and to neurodevelopmental and neurodegenerative diseases.

It shifts how we think about the neuronal genome. 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."

Professor Mineko Kengaku, WPI-iCeM

The work was a collaboration between Kyoto University and groups at the University of Tokyo, the University of Osaka, the National University of Singapore, and the Tokyo Metropolitan Institute of Medical Science.