As the brain develops, newly formed neurons pass through dense tissue to their final destination in the cerebral cortex, where they become part of the brain’s communication network. This movement allows cells to pass through narrow gaps between fibers and adjacent cells.
New research published in nature It revealed an unintended consequence of that process. Researchers at the Kyoto University Institute for Cellular and Integrated Sciences (WPI-iCeMS) and collaborating institutions have discovered that migrating neurons routinely experience significant DNA damage. Specifically, cells develop double-strand breaks. This is severe DNA damage that breaks both strands of the DNA double helix.
Although double-strand breaks are usually associated with mutations, cell dysfunction, and even cell death, researchers have discovered that they are a normal part of brain cortex development. In a healthy brain, damage is quickly repaired before it causes permanent problems.
“The developing brain appears to have evolved to withstand and efficiently repair damage to neurons,” says WPI-iCeMS professor Mineko Kengaku, who led the study. “But by understanding the limits of that tolerance and what happens when repair is incomplete, we can move closer to understanding a variety of neurological conditions.”
DNA damage during neuron migration
To investigate how this damage occurs, the researchers recreated the physical challenges faced by developing neurons. They guided neurons through tiny microchannels designed to mimic the confined spaces found in growing brain tissue.
The research team used fluorescent markers to observe the double-stranded DNA breaks that appear as neurons move through the channel. The damage gradually disappeared as cells emerged from the other side. Most damage was repaired within 24 hours, and neurons continued to function normally.
Researchers identified topoisomerase IIβ as the cause of the damage. Topoisomerase IIβ is an enzyme that normally helps cells deal with stress within their DNA. Under normal conditions, enzymes temporarily cut DNA strands to release twists and tensions caused by daily cellular activities, and then reconnect the DNA strands.
This process is similar to cutting, untangling, and reconnecting a tangled cable. But when neurons are exposed to mechanical stress as they pass through narrow spaces, enzymes can become trapped midway through the process, leaving some of their DNA destroyed. Cells then use a repair mechanism called nonhomologous end joining to reconnect the damaged DNA ends.
Why do neurons recover while other cells do not?
The researchers found that DNA damage in neurons is different from damage seen in certain cancer cells that traverse the same microchannels. In cancer cells, DNA damage tends to occur more randomly and can disrupt normal cell activity or cause cell death.
In contrast, DNA breaks in neurons were mainly concentrated in genomic regions that are not actively involved in important gene functions. Most essential genes are preserved, allowing cells to maintain normal function despite temporary damage.
When DNA repair is insufficient
To examine the effects of failed repair, the researchers engineered mice in which newly formed cerebellar neurons lacked ligase 4, an enzyme required to repair DNA breaks.
The mice developed normally and no obvious abnormalities were observed initially. However, as he reached adulthood, he began to experience mild but progressively worsening balance problems. These symptoms are similar to those seen in certain human diseases associated with genomic instability that affect the cerebellum.
Clues about brain diversity and disease
The findings suggest that DNA breakage and repair may play a larger role in brain biology than previously recognized. Researchers now want to understand whether these early DNA changes contribute to differences between individual neurons and whether they influence future neurodevelopmental and neurodegenerative diseases.
“This changes the way we think about neuronal genomes,” says Professor Kengaku. “All neurons originate from the same DNA, but DNA damage and repair can create small genetic differences between individual neurons through small mechanical journeys. Part of their history can be written into the genome itself.”
This study was carried out in collaboration with Kyoto University, the University of Tokyo, Osaka University, the National University of Singapore, and the Tokyo Metropolitan Institute of Medical Science.
