DNA polymerase β (Polβ) has been implicated in base excision repair in mammalian cells. However, the physiological significance of this enzyme in the body remains unclear. Here, we demonstrate that mice carrying a targeted disruption of the Polβ gene showed growth retardation and died of a respiratory failure immediately after the birth. Histological examination of the embryos revealed defective neurogenesis characterized by apoptotic cell death in the developing central and peripheral nervous systems. Extensive cell death occurred in newly generated post-mitotic neuronal cells and was closely associated with the period between onset and cessation of neurogenesis. These findings indicate that Polβ plays an essential role in neural development.

Transcriptional regulation of gene expression is thought to play a pivotal role in activity-dependent neuronal differentiation and circuit formation. Here, we investigated the role of histone deacetylase 9 (HDAC9), which regulates transcription by histone modification, in the development of neocortical neurons. The translocation of HDAC9 from nucleus to cytoplasm was induced by an increase of spontaneous firing activity in cultured mouse cortical neurons. This nucleocytoplasmic translocation was also observed in postnatal development in vivo. The translocation-induced gene expression and cellular morphology was further examined by introducing an HDAC9 mutant that disrupts the nucleocytoplasmic translocation. Expression of c-fos, an immediately-early gene, was suppressed in the mutant-transfected cells regardless of neural activity. Moreover, the introduction of the mutant decreased the total length of dendritic branches, whereas knockdown of HDAC9 promoted dendritic growth. These findings indicate that chromatin remodeling with nucleocytoplasmic translocation of HDAC9 regulates activity-dependent gene expression and dendritic growth in developing cortical neurons.

The transcription factor, cAMP response element-binding protein (CREB) is known to regulate gene expression in neuronal activity-dependent processes. However, its spatiotemporal interactions with the genome remain unknown. Single-molecule imaging in cortical neurons revealed that fluorescent-tagged CREB spots frequently reside at fixed nuclear locations in the time range of several seconds. Neuronal activity had little effect on the CREB residence time, but increased the rapid and frequent reappearance of long-residence CREB spots at the same nuclear locations. Thus, activity-dependent transcription is attributable to frequent binding of CREB to specific genome loci.