||Matsuda T * (co-corresponding author)., Irie T., Katsurabayashi S., Hayashi Y., Nagai T., Hamazaki N., Adefuin AMD., Miura F., Ito T., Kimura H., Shirahige K., Takeda T., Iwasaki K., Imamura T. & Nakashima K*., Pioneer Factor NeuroD1 Rearranges Transcriptional and Epigenetic Profiles to Execute Microglia-Neuron Conversion, Neuron, 101, 472-485, 2019.01, Minimal sets of transcription factors can directlyreprogram somatic cells into neurons. However,epigenetic remodeling during neuronal reprogram-ming has not been well reconciled with transcrip-tional regulation. Here we show that NeuroD1achieves direct neuronal conversion from mouse mi-croglia bothin vitroandin vivo. Exogenous NeuroD1initially occupies closed chromatin regions associ-ated with bivalent trimethylation of histone H3 atlysine 4 (H3K4me3) and H3K27me3 marks in micro-glia to induce neuronal gene expression. These re-gions are resolved to a monovalent H3K4me3 markat later stages of reprogramming to establish theneuronal identity. Furthermore, the transcriptionalrepressorsScrt1andMeis2are induced as NeuroD1target genes, resulting in a decrease in the expres-sion of microglial genes. In parallel, the microglialepigenetic signature in promoter and enhancerregions is erased. These findings reveal NeuroD1pioneering activity accompanied by global epige-netic remodeling for two sequential events: onset ofneuronal property acquisition and loss of the micro-glial identity during reprogramming..
||Murao N., Matsubara S., Matsuda T., Noguchi H., Mutoh T., Mutoh M., Koseki H., Namihira M. & Nakashima K., Np95/Uhrf1 regulates tumor suppressor gene expression of neural stem/precursor cells, contributing to neurogenesis in the adult mouse brain., Neurosci Res, 2018.08.
||Sakai A., Matsuda T (equal first authorship)., Doi H., Nagaishi Y., Kato K. & Nakashima K. , Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice, Proc Natl Acad Sci USA, 2018.04, Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero..
||Uezono N., Zhu Y., Fujimoto Y., Yasui T., Matsuda T., Nakajo M., Abematsu M., Setoguchi T., Mori S., Takahashi H.K., Komiya S., Nishibori M. & Nakashima K., Prior treatment with anti-High Mobility Group Box-1 antibody boosts human neural stem cell transplantation-mediated functional recovery after spinal cord injury, Stem Cells, 2018.03.
||Kimura A., Matsuda T* (co-corresponding author)., Sakai A., Murao N. & Nakashima K*., HMGB2 expression is associated with transition from a quiescent to an activated state of adult neural stem cells. , Deve Dyn, 2017.08.
||5. Yasui T., Uezono N., Nakashima H, Noguchi H., Matsuda T., Noda-Andoh T., Okano H. & Nakashima K, Hypoxia epigenetically confers astrocytic differentiation potential on human pluripotent cell-derived neural precursor cells, Stem Cell Reports, 2017.06.
||Brulet R., Matsuda T., Zhang L., Miranda C., Giacca M., Kaspar B.K., Nakashima K. & Hsieh J., NEUROD1 instructs neuronal conversion in non-reactive astrocytes, Stem Cell Reports, 2017.03.
||Noguchi H., Murao N., Kimura A., Matsuda T., Namihira M. & Nakashima K., DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus., J. Neurosci, 2016.05.
||Matsuda T., Murao N., Katano Y., Juliandi B., Kohyama J., Akira S., Kawai T. & Nakashima K, TLR9 signaling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus, Nat Commun, 2015.03.
||Yuasa K., Matsuda T. (equal first authorship) & Tsuji A., Functional regulation of transient receptor potential canonical 7 by cGMP-dependent protein kinase Iα., Cell. Signal., 2011.01.