Neuronal DNA breaks as the cells migrate during development, though enzymes later fix that damage to preserve function, according to a study published in Nature last month.
“DNA damage is something that you think about when you might have an X-ray or when you go flying in a plane,” says David Rowitch, deputy director of basic and translational research at Cedars-Sinai Guerin Children’s and professor of pediatrics at the University of Cambridge, who was not involved in the study. “What people maybe don’t understand as well is [that] during development, there’s a lot of DNA damage that normally occurs.”
During human fetal development, neurons travel from the ventricular zone to take up residence elsewhere in the brain and nervous system. This trek “is a risky process; neurons seem to have a very dangerous trip,” says study investigator Mineko Kengaku, professor of developmental biology at Kyoto University’s Institute for Integrated Cell-Material Sciences.
The nuclei of migrating cells can become deformed as the cells pass through tight intercellular spaces, previous work shows. In cancer and immune cells, this migration can rupture the nuclear envelope. That doesn’t happen in neuronal nuclei, but they still elongate, rotate and distort during their travels, according to the live-cell imaging presented in the new work.
Kengaku and her colleagues forced fetal mouse cerebellar granule neurons to squeeze through microfluidic channels etched into a 2D chip, approximating the cells’ journey in vivo. Fluorescent tags marked the cells’ nuclear envelope and DNA damage in distinct colors.
As the nucleus of each cell is distorted during the cells’ passage, most acquire double-stranded DNA breaks, the study shows. An enzyme called topoisomerase 2-beta covalently binds the breaks, which the cells then mend via non-homologous end-joining using the enzyme ligase 4, the primary mechanism by which cells repair breaks without a template strand.
Cerebellar granule neurons from mice missing the repairing ligase changed their expression of only 336 genes. These knockout mice developed normally, aside from subtle differences in their motor functions later in life. The results suggest that “DNA damage is inevitable,” Kengaku says, but the neurons have a “mechanism to make the DNA damage in safe genomic regions.”