ー 神経発生から精神疾患まで ー

Epigenetic regulations
ー From the neural development to psychiatric disorders ー
Epigenetic mechanisms underlying the generation and differentiation of neural stem cells

○Seiji Hitoshi1,2
滋賀医科大学生理学講座統合臓器生理学1, 生理学研究所分子神経生理部門2
Department of Physiology, Shiga University of Medical Science1, Neurobiology & Bioinformatics, NIPS2

Epigenetic regulation of gene expression plays pivotal roles in early development of mammalian embryos and in the generation of central nervous tissue. We have been studying epigenetic mechanisms that modify the activation of Notch signaling, which is critical for the generation, maintenance, and differentiation of neural stem cells, and we have identified two epigenetic modifications; DNA demethylation by Glial cells missing (Gcm) genes and histone H2B monoubiquitylation by Ring finger protein 20 (Rnf20). Gcm genes are required for the transition from primitive to definitive neural stem cells. Interestingly, the transient expression of Gcm genes in mouse embryos at around E7.5 induces the demethylation of the promoter of Hes5 gene, one of Notch effector genes, in a genome duplication-independent fashion. On the other hand, we have recently found that Rnf20 is indispensable for embryonic development beyond the blastocyst stage and that it regulates the cell cycle time of ES as well as neural stem cells by activating the expression of several genes including Hes5. I will present recent data of our research on these topics.
Effects of an antiepileptic valproic acid on the development and regeneration in the central nervous system

○Kinichi Nakashima1,2
奈良先端科学大学分子神経分化制御学1, 九大院・医・応用幹細胞医科学2
Laboratory of Molecular Neuroscience, Nara Institute of Science and Technology1, Dept Stem Cell Biol Med, Kyushu Univ, Fukuoka2

The mammalian brain contains multipotent neural stem cells (NSCs) that can self-renew and give rise to all three major cell types in the nervous system, i.e., neurons, astrocytes and oligodendrocytes. It has become apparent that epigenetic modifications including histone acetylation play critical roles in fate specification of NSCs. We have previously reported that an antiepileptic and histone deacetylase (HDAC) inhibitor valproic acid (VPA) promotes neuronal differentiation of NSCs. Taking advantage of this function, we have developed a novel method to treat spinal cord injury referred to as HINT (Hdac Inhibitor and NSC Transplantation) method. We could supply newly generated neurons from transplanted NSCs in the injured spinal cord with VPA administration. The transplant-derived neurons reconstructed broken neuronal circuits, thereby allowing them to transmit signals in a relay manner. However, VPA does not always elicit favorable effects. Prenatal exposure to VPA has been reported to impair postnatal cognitive function of children from epileptic mother. Nevertheless, its pathology and proper treatment to minimize the effects remain unknown. We here report that the postnatal cognitive function impairment is largely attributable to a reduction of adult neurogenesis and neuronal abnormalities in the hippocampus, of which could be ameliorated by voluntary running.
How epigenetics contribute to pathogenesis of neurodegeneration?

○Atsushi Iwata1
Dept Molecular Neuroscence on Neurodegeneration, The Univ of Tokyo1

Since the discovery of responsible gene for various neurodegenerative diseases, huge progress has been made in understanding of the disease molecular pathomechanisms. However, the vast majority of neurodegenerative diseases consists of sporadic cases that genetic mutations found in familial cases have never been discovered. For instance, familial Alzheimer's disease (AD) is caused by mutations in APP, PSEN1 or PSEN2 which mutations are absent in sporadic cases. Nonetheless, pathological features of sporadic AD are almost indistinguishable from familial AD, which suggests that they share similar molecular pathomechanism. I hypothesized that this could be mediated by epigenome alterations of the genes responsible for familial cases. Intensive analysis of post-mortem brains revealed disease specific CpG methylation abnormality in sporadic Parkinson's Disease and AD cases. I will discuss these observational results and also try to extend those to a novel hypothesis by some in vitro experiments.
Comprehensive genome and epigenome analyses of neuronal genomes in major psychiatric disorders

○岩本和也1, 加藤忠史2
○Kazuya Iwamoto1, Tadafumi Kato2
東京大学大学院医学系研究科分子精神医学講座1, 理化学研究所脳科学総合研究センター精神疾患動態研究チーム2
Department of Molecular Psychiatry, Graduate School of Medicine, the University of Tokyo1, RIKEN BSI2

Despite the extensive efforts, genetic factors involved in major psychiatric disorders such as bipolar disorder and schizophrenia remain largely unknown. Accumulating evidence suggest that genomic DNA in the human brain exhibited the genetic and epigenetic variations. These included chromosomal aneuploidy and retrotransposition in the neuronal progenitor cells for the genetic variations, and various cytosine modifications such as methylation and hydroxymethylation for the epigenetic variations. Although biological significance of genetic and epigenetic variations for neuronal function remains unclear, altered frequencies and/or patterns of the variations may have pathophysiological consequence for the psychiatric disorders. We have been exploring the both genetic and epigenetic variations in the brains of patients with bipolar disorder or schizophrenia. Currently, we found the altered retrotransposition activity in the neuronal genome of patients with schizophrenia by a Taqman-based quantitative PCR assay, and altered DNA methylation in the brains of patients with bipolar disorder and schizophrenia by MBD2B-based methylated DNA enrichment followed by tiling array analysis. Our results suggest that further genetic and epigenetic analyses in the brain genome will not only reveal the molecular basis of neuronal function, but also contribute to understand the pathophysiology of psychiatric disorders.
Modeling Human Psychiatric Disease using reprogrammed somatic cells
○Fred H. Gage1
Laboratory of Genetics LOG-G, Salk Institute for Biological Studies1

Cellular programming and reprogramming technology (CPART) has provided a new way to investigate human development and disease. This technology is particularly useful for diseases in which the affected tissue is not available for cell purification and where aspects of cell development are crucial for the pathology. The central nervous system (CNS) is a good example of tissue that falls into this category. Modeling human brain diseases using induced pluripotent stem cells (iPSC) or induced neural cells (iN) has remarkable potential to generate insights into understanding disease mechanisms and opening new avenues for clinical intervention. Researchers now have the opportunity to study human disease in living, developing neural cells that carry the disease-specific genetic variants that are present in the patient. In addition, CPART represents a fresh approach for developing original diagnostic tools and obtaining novel drug candidates for CNS therapy. In order for CPART to be successful/useful, our underlying assumption is that, cellular deficiencies can be measured in vitro, recapitulating the phenotype that is relevant to human brain disease. Success requires that in vitro modeling is robust enough to detect a reliable and statistically meaningful difference between phenotypically normal and abnormal cells derived using CPART. This is particularly important in our view because there could be diseases where the variability of phenotypes will be too large to achieve reliable statistical significance. I will present several potential uses for modeling neurological and psychiatric diseases, as well as highlighting areas of caution and opportunities for improvement.

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