島根大学医学部医学科発生生物学Department of Anatomy, Faculty of Medicine, Shimane University― 239 ―Gene expression regulated by spatial chromatin organization and nuclear architecture plays crucial roles in the development of the brain. We have focused on the role of the cohesin complex, which is chromosome-associated multi-subunit proteins, in embryonic and adult neurogenesis.Cohesin is a highly conserved nuclear protein complex composed of four subunits, Smc1, Smc3, Scc3, and Scc1 (Rad21), which form a ring structure. The cohesin complex is well known for its role in sister chromatid cohesion to maintain the proper cell cycle process, through its inclusion of the sister chromatid into its ring-like structure. However, the cohesin subunit proteins continue to be expressed in postmitotic cells, including NeuN-positive neurons. Cohesin mediates chromatin loop formation, which has a role in regulating gene expression. Loss of cohesin function causes disruptions in chromatin loops, with subsequent effects on transcriptional regulation. Mutations that perturb the function of cohesin or the proteins that regulate cohesin function cause Cornelia de Lange syndrome (CdLS), a rare malformation syndrome characterized by mental retardation, limb abnormalities, and distinctive facial features. Most of these mutations do not cause overt defects in cohesion or chromosomal segregation.To investigate the potential role of cohesin in terminally differentiated cells in vivo, we generated conditional Smc3-knockout mice. We observed craniofacial abnormality and decreased spine density in cortical neurons of heterozygous Smc3-knockout mice. Heterozygous Smc3-knockout mice exhibited increased anxiety-related behavior, which is consistent with a symptom of Cornelia de Lange syndrome. Thus, neuronal cohesin contributes to neural network formation, and cohesin deficiency leads to higher brain dysfunction.Abstractゲノム解析を活用した神経変性メカニズムの解明とAnalysis of spatial chromatin organization in the central nervous system治療法の開発藤田 幸Yuki Fujita
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