Migrating cortical neurons incur targeted Top2β double-strand breaks at non-coding loci during confined passage, Kyoto–Nature study shows
Neurons must transiently fracture their own DNA at non-coding sites to navigate the packed embryonic brain; efficient repair preserves function while incomplete repair seeds later neurological disease. The work elevates mechanical stress from a physical nuisance to a regulated genomic event.
Unresolved questions include whether the same Top2β-trapping mechanism operates in human gyrencephalic cortices and whether low-level unrepaired breaks accumulate over decades to elevate Alzheimer’s or ALS risk. Longitudinal single-cell whole-genome sequencing of human fetal cortex at 12–20 post-conception weeks will be required to quantify break frequency and repair fidelity in vivo.
Kengaku lab: Single-cell long-read sequencing of 500 human cortical neurons from 15–22 week fetuses will detect Top2β footprint mutations at >2 % allele frequency in non-coding regions within 24 months.
Sources (3)
- [1]Primary Source(https://www.nature.com/articles/s41586-026-07892-4)
- [2]Supporting Source(https://www.cell.com/neuron/fulltext/S0896-6273(19)30612-8)
- [3]Supporting Source(https://www.nature.com/articles/s41586-018-0575-1)