2022 Fiscal Year Final Research Report
Molecular mechanisms for spatiotemporal and target specific regulation of neuronal synapse formation
| Project/Area Number |
20H03350
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 46020:Anatomy and histopathology of nervous system-related
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| Research Institution | University of Toyama |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
和泉 宏謙 富山大学, 医学部, 技術専門職員 (00377342)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | シナプス / シナプスオーガナイザー / マイクロエクソン / 神経発達障害 |
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| Outline of Final Research Achievements |
Protein tyrosine phosphatase δ (PTPδ) is a presynaptic organizer and exists in various splice variants generated by alternative microexons' splicing. Each PTPδ variant is responsible for target-specific synapse formation by binding to different type of postsynaptic ligands. We found that microexon-derived peptides are inserted into the interaction interface with ligand proteins to ensure selective binding and synaptic target specificity. In fact, knock-in mutant mouse strains carrying point mutations in the specific interaction interface to disrupt the selective interaction and balancing mechanism among different types of synapse organizers exhibited excitatory and inhibitory synaptic imbalance and behavioral abnormalities associated with neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability.
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| Free Research Field |
分子神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
マイクロエクソンは3-27ヌクレオチドの極めて短いエクソンであり、脊椎動物の神経細胞で選択的に利用されることから、その機能に注目が集まっていた。シナプスオーガナイザー遺伝子の持つマイクロエクソン由来ペプチドが中枢シナプス形成時の標的選別に重要な役割を担うことを見出し、マイクロエクソンの新しい機能を提案した点が本研究の学術的意義である。またシナプスオーガナイザー間の競合バランスの変調が神経発達障害の発病の要因となることを示した。神経発達障害の新たな治療・創薬標的として、マイクロエクソン選択機構やシナプスオーガナイザー間の競合機構の重要性を提示した点が本研究の社会的意義である。
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