A study in Nature reports that newborn neurons can incur double-strand DNA breaks while squeezing through tight spaces in the developing brain, and that healthy cells typically repair most of this damage within about a day.
The developing brain forces newly formed neurons to travel through tightly packed tissue to reach their destinations, including the cerebral cortex, pushing through narrow gaps between fibers and neighboring cells.
A study published in Nature by researchers led by Professor Mineko Kengaku at Kyoto University’s Institute for Integrated Cell-Material Sciences (WPI-iCeMS) reports that this confined migration is associated with double-strand breaks—one of the most severe types of DNA damage—occurring in migrating neurons.
To probe the mechanism, the team guided neurons through microchannels designed to mimic the cramped spaces of developing brain tissue. Using fluorescent markers, they observed DNA breaks emerging as neurons moved through these channels and diminishing after the cells exited; the report says most breaks were repaired within 24 hours and that neurons continued to function normally.
The researchers attribute the damage to topoisomerase IIβ, an enzyme that normally makes transient cuts in DNA to relieve torsional stress before re-ligating the strands. Under mechanical stress during squeezing, the study says, the enzyme can become trapped in an intermediate state, leaving DNA ends that are then rejoined through the non-homologous end-joining repair pathway.
The report also describes a difference from patterns seen in cancer cells migrating through similar confinement: neuronal breaks were concentrated in genomic regions less likely to disrupt essential gene functions, which the authors suggest may help neurons tolerate transient damage.
To examine what happens when repair is impaired, the researchers engineered mice in which newly formed cerebellar neurons lacked DNA ligase 4, an enzyme required for repairing DNA double-strand breaks. According to the study, the mice appeared to develop normally early on but later showed mild, progressively worsening balance problems in adulthood—symptoms the authors say resemble features of some human conditions tied to genome instability affecting the cerebellum.
“The developing brain appears to have evolved to tolerate and repair the neuronal damage efficiently,” Kengaku said.
The work was reported as a collaboration involving Kyoto University, the University of Tokyo, Osaka University, the National University of Singapore, and the Tokyo Metropolitan Institute of Medical Science.
