Life science
Healthcare, Drug discovery

Molecular mechanism of genome stability in postnatal
brain development
Graduate School of Frontier Biosciences
SA Associate Professor Noriyuki Sugo
Researchmap https://researchmap.jp/norisugo?lang=en

Life science

Abstract
Genome stability is essential for brain development and function, as de novo mutations during neuronal development cause
psychiatric disorders. However, the contribution of DNA repair togenome stability in postnatal neurons remains elusive. Here, we
demonstrate that DNA repair protein DNA polymerase β (Polβ)
is involved in hippocampal pyramidal neuron differentiation via a
TET-mediated active DNA demethylation during early postnatal
stages using conditional knockout mice. Polβ deficiency induced
extensive DNA double-strand breaks (DSBs) in hippocampal pyramidal neurons. Inhibition of DNA demethylation by suppressing
TET expression diminished DSB formation. Conversely, its induction by TET1 catalytic domain overexpression increased DSBs inneurons. Furthermore, the damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation. Comprehensive behavioral analyses revealed impaired spatial
memory and anxiety behavior in adulthood. Thus, Polβ maintains
genome stability in the active DNA demethylation that occurs during early postnatal neuronal development, thereby contributing todifferentiation and subsequent learning and memory.

impaired spatial reference memory, contextual fear memory andanxiety behavior in adulthood.

▍ Significance of the research and Future perspective
Polβ maintains genome stability in the active DNA demethylation that occurs during early postnatal neuronal development,
thereby contributing to differentiation and subsequent learningand memory in adult. It is expected to lead to understanding of themechanism of mutagenesis that causes neuropsychiatric disorders
and to the development of preventive medical methods.

▍ Background & Results
Genome stability is essential for brain development and function,
as de novo mutations during neuronal development cause psychiatric disorders such as autism spectrum disorders. Polβ is a corecomponent of the base excision repair pathway, and also plays
a role in the active DNA demethylation process as an epigenetic
regulation. Studies using conventional Polβ-deficient mice show
increased neuronal apoptosis during the period of neurogenesis
in the developing nervous system rather than in other tissues, andthe mice die just after birth. Further, our previous study focusing on
spatiotemporal roles using forebrain-specific conditional KO miceindicates that Polβ deficiency in neural progenitors rather than in
postmitotic neurons specifically leads to an increase of DNA double-strand breaks (DSBs) and apoptosis in the embryonic neocortex (Onishi et al., 2017). However, the contribution of DNA repair
to genome stability in postnatal neurons remains elusive. Here, wedemonstrate that Polβ is involved in hippocampal pyramidal neuron differentiation via a TET-mediated active DNA demethylation
during early postnatal stages using conditional knockout mice, inwhich forebrain postmitotic excitatory neurons lack Polβ expression. Polβ deficiency induced extensive DSBs in hippocampal
pyramidal neurons, and to a lesser extent in neocortical neurons,
during a period in which decreased levels of 5-methylcytosine
were observed in genomic DNA. Inhibition of the hydroxylation of
5-methylcytosine by expression of microRNAs miR-29a/b-1 diminished DSB formation. Conversely, its induction by TET1 catalytic
domain overexpression increased DSBs in neocortical neurons.
Furthermore, the damaged hippocampal neurons exhibited aberrant neuronal gene expression profiles and dendrite formation,
but not apoptosis. Comprehensive behavioral analyses revealed

Fig. 1 Polβ deficiency influences postnatal neuronal differentiation and subsequent learning and memory in adulthood.

Fig. 2 Increased DNA double-strand breaks in Polβ-deficient hippocampal neurons.

Fig. 3 Polβ contributes to active DNA demethylation that occurs during early
postnatal neuronal differentiation.

P a t e n t
Uyeda, A; Onishi, K; Hirayama, T et al. Suppression of DNA Double-Strand Break Formation by DNA Polymerase β in Active DNA Demethylation is
Required for Development of Hippocampal Pyramidal Neurons. J Neurosci. 2020; 40: 9102-9027. doi: 10.1523/JNEUROSCI.0319-20.2020
Onishi, K; Uyeda, A; Shida, M et al. Genome Stability by DNA polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in CorticalDevelopment. J Neurosci. 2017; 37: 8444-8458. doi: 10.1523/JNEUROSCI.0665-17.2017
UR
L https://www.fbs.osaka-u.ac.jp/ja/research_results/papers/detail/1008
K e y w o r d neuroscience, DNA repair, epigenetics, learning and memory, psychiatric disorders
Tr e a t i s e