Newborn nerve cells experience widespread DNA damage as they migrate through crowded, narrow spaces in the developing brain cortex, according to a study published in Nature by researchers at Kyoto University's Institute for Integrated Cell-Material Sciences and collaborators. The research team found that these neurons sustain double-strand breaks—where both strands of the DNA helix are severed—during their journey, but that healthy brains efficiently repair this damage before it causes harm.
"The developing brain appears to have evolved to tolerate and repair the neuronal damage efficiently," said 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."
To simulate neuron migration, researchers guided neurons through microchannels mimicking tight spaces in brain tissue. Using fluorescent markers, they observed DNA double-strand breaks forming as cells passed through these channels and disappearing after arrival on the other side. Most breaks were repaired within 24 hours with no lasting effects on cell function.
The study traced these DNA breaks to Topoisomerase IIβ, an enzyme responsible for making controlled cuts in DNA to relieve torsional strain during cellular activity. Under mechanical stress from migration, this enzyme can become stuck mid-process, leaving broken ends that are then repaired by a pathway known as non-homologous end joining.
In contrast to some cancer cells—which show random and harmful DNA damage under similar conditions—the neuronal damage occurred mainly in non-critical genome regions rather than active genes, preserving overall function. When researchers engineered mice lacking Ligase 4—a key repair enzyme—in new cerebellar neurons, the animals developed normally but later showed mild balance difficulties reminiscent of human genome instability syndromes affecting the cerebellum.
The findings raise questions about whether early-life neuronal DNA breaks contribute to individual differences among neurons or play a role in neurodevelopmental and neurodegenerative diseases.
