Faulty Gene Impairs Brain Development

Using genetically engineered mice, researchers in Japan have demonstrated that DNA repair is an essential process for normal brain development.

AsianScientist (Sept. 5, 2017) – Scientists in Japan have discovered that the loss of DNA repair in neurons results in impaired brain development. They publish their work in the Journal of Neuroscience.

DNA is the code that programs every event in the body. It is constantly replicated during development and throughout the lifetime of an organism. Hence, fidelity during DNA replication is essential to prevent the accumulation ‘coding errors’, and the body has many DNA repair mechanisms to correct such errors.

In this study, researchers from Osaka University in Japan showed that a defect in one type of DNA repair machinery, DNA polymerase β (Polβ), causes underdevelopment of the brain’s cortices and axonal network. Mice lacking Polβ showed a large number of double-strand DNA breaks (DSBs) in neural progenitors, the stem cells that eventually produce neurons.

Consequently, many immature neurons underwent programmed cell death. Furthermore, the mice showed defects in the development of specific brain anatomy and the growth of axons in specific cell types, suggesting underdevelopment of the cortex and impaired neural networking.

“Polβ is responsible for repairing DNA base damage in the brain. Because many neurological disorders are associated with de novo mutations, we wanted to study how loss of Polβ affects neuronal development,” said Assistant Professor Noriyuki Sugo, an expert in the study of Polβ in brain development.

“We found evidence that Polβ has a role in the development of the brain, but not other organs, and that its defect causes catastrophic DSBs. The resultant effect is cell death in certain regions of the developing cortex,” he added.

These regions represent one of the earliest stages of cortical development, and the generation of cortical neurons is fundamental to proper neural networking.

“We found that Polβ deficiency led to higher neuronal cell death in deeper layers than upper layers of the cortex. The deeper layers were thinner,” said Sugo.

Neurons formed in these deeper layers are thought to be essential to the early stages of neural networking. Thus, even if the cells manage to escape death, the brain circuitry is likely to be compromised.

Finally, proper development depends on both genetic and epigenetic factors. The correction of DNA damage by Polβ is an example of genetic regulation. In addition, the researchers found that DNA demethylation, an example of epigenetic regulation, is also abnormal in mice deficient in Polβ expression.

Collectively, the findings are strong evidence for the importance of Polβ on proper gene expression in cortical development and provide a new target for the study of associated syndromes and disorders.

“The brain is actively constructed in embryonic stages. Neural progenitors produce many neurons, their genomic DNA is constantly processed. Defects in Polβ function could be a new target for explaining cortical developmental disorders,” Sugo said.

The article can be found at: Onishi et al. (2017) Genome Stability by DNA Polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development.


Source: Osaka University; Photo: Shutterstock.
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