Graduate School of Frontier Biosciences, Osaka University

Japanese

Genome Stability by DNA polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development

Journal J Neurosci (2017)
Authors Onishi K (1), Uyeda A (1), Shida M (1), Hirayama T (1, 2), Yagi T (1, 2), Yamamoto N (1), Sugo N (1)
  1. Graduate School of Frontier Biosciences, Osaka University, Osaka, 565-0871, Japan
  2. Japan Science and Technology Agency-Core Research for Evolutional Science and Technology, CREST
Title Genome Stability by DNA polymerase β in Neural Progenitors Contributes to Neuronal Differentiation in Cortical Development
PubMed 28765330
Laboratory Cellular and Molecular Neurobiology Group 〈Prof. Yamamoto〉
Abstract DNA repair is crucial for genome stability in the developing cortex, as somatic de novo mutations cause neurological disorders. However, how DNA repair contributes to neuronal development is largely unknown. To address this issue, we studied the spatiotemporal roles of DNA polymerase β (Polβ), a key enzyme in DNA base excision repair (BER) pathway, in the developing cortex using distinct forebrain-specific conditional knockout mice, Emx1-Cre/Polβfl/fl and Nex-Cre/Polβfl/fl mice. Polβ expression was absent in both neural progenitors and postmitotic neurons in Emx1-Cre/Polβfl/fl mice, while only postmitotic neurons lacked Polβ expression in Nex-Cre/Polβfl/fl mice. We found that DNA double-strand breaks (DSBs) were frequently detected during replication in cortical progenitors of Emx1-Cre/Polβfl/fl mice. Increased DSBs remained in postmitotic cells, which resulted in p53-mediated neuronal apoptosis. This neuronal apoptosis caused thinning of the cortical plate, although laminar structure was normal. In addition, accumulated DSBs also affected growth of coticofugal axons but not commissural axons. These phenotypes were not observed in Nex-Cre/Polβfl/fl mice. Moreover, cultured Polβ-deficient neural progenitors exhibited higher sensitivity to the base-damaging agent methylmethanesulfonate, resulting in enhanced DSB formation. Similar damage was found by vitamin C treatment, which induces TET1-mediated DNA demethylation via 5-hydroxymethylcytosine. Taken together, genome stability mediated by Polβ-dependent BER is crucial for the competence of neural progenitors, thereby contributing to neuronal differentiation in cortical development.