Scientists Discover Neurons Must Break DNA to Build the Developing Brain - Video

New brain cells may briefly damage their own DNA as they squeeze through the crowded developing brain, according to a new study published in Nature. Researchers found that these DNA breaks are a normal part of brain development and are usually repaired within a day, allowing neurons to continue developing normally.

During early brain development, newly formed neurons must migrate through tightly packed brain tissue to reach their final positions in the cerebral cortex, where they form neural circuits. To investigate what happens during this journey, researchers from Kyoto University and collaborating institutions recreated these confined conditions by guiding neurons through tiny microchannels that mimic the narrow spaces in the developing brain.

The team found that as neurons squeezed through these tight spaces, they frequently developed DNA double-strand breaks—one of the most severe forms of DNA damage, in which both strands of the DNA helix are cut. However, once the neurons completed their migration, most of the damage was repaired within 24 hours, and the cells continued to function normally.

Further experiments showed that the damage was caused by Topoisomerase IIβ, an enzyme that normally relieves twisting and mechanical stress in DNA by temporarily cutting and reconnecting DNA strands. Under the physical strain of migration, the enzyme sometimes became trapped before completing the repair, leaving DNA temporarily broken. The cells then repaired these breaks using a process called non-homologous end joining.

Unlike cancer cells, where similar mechanical stress can cause widespread and harmful DNA damage, neurons largely confined these breaks to regions of the genome that are not essential for critical gene activity. This selective pattern likely helps preserve normal brain development despite the temporary DNA damage.

To understand what happens when repair fails, researchers engineered mice lacking Ligase 4, a key DNA repair enzyme, in newly formed cerebellar neurons. Although the mice developed normally, they gradually developed mild balance problems in adulthood, resembling certain human neurological disorders linked to defective DNA repair.

The researchers believe these findings reshape our understanding of brain development, suggesting that temporary DNA damage and repair may be a natural part of neuronal maturation.

REFERENCE: Zhejing Zhang, Andres Canela, Junko Kurisu, Peilin Zou, Takumi Kawaue, Naotaka Nakazawa, Noriko Takeda, Mai Saeki, Masaki Utsunomiya, Merve Bilgic, Fumiyoshi Ishidate, Gianluca Grenci, Takahiro Furuta, Yusuke Kishi, Hiroyuki Sasanuma, Mineko Kengaku. Confined migration induces non-lethal DNA damage in developing neurons. Nature, 2026; DOI: 10.1038/s41586-026-10648-8