TOP ＞ 公募シンポジウム

公募シンポジウム 神経突起構造の制御機序から拡がる生理機能と病態の理解 7月7日（金）　10:40-12:40　Room E 2SY④-1 環境刺激に応じた有髄軸索の機能と形態の制御 Structural and functional regulation of myelinated axons in response to sensory stimuli 長内　康幸1,2, 大野　伸彦1,3 1. 自治医科大学　医学部解剖学講座組織学部門, 2. モナッシュ大学ARMI, 3. 生理学研究所　超微形態研究部門 Yasuyuki Osanai1,2, Nobuhiko Ohno1,3 1. Division of Histology and Cell Biology, Jichi Medical Univ., Shimotsuke, Japan, 2. ARMI, Monash Univ., Clayton, Australia, 3. Division of Ultrastructural Research, NIPS, Okazaki, Japan Formation and structural regulation of myelin sheath is critical for basic and higher brain functions, and myelination is modulated by activities of the axons. While each oligodendrocyte produces myelin sheathes around multiple neuronal axons, the regulation of myelin formation and structures at the single oligodendrocyte level has been unclear, partly because it was challenging to visualize and identify individual oligodendrocytes with their myelin sheathes and the axons myelinated by them. Using a new rabies virus-mediated oligodendrocyte labeling and 3-dimensional electron microscopic analyses, we identified axons myelinated by a single oligodendrocyte. We revealed that all myelin sheaths produced by a single oligodendrocyte were shortened depending on abundance of inactive axons caused by sensory deprivation. The altered myelin morphology was not restored by rearing under the normal condition. In addition, some oligodendrocytes in the white matter preferentially myelinated a particular set of axons characterized by the origins and sizes of the axons, whereas the reduction of neuronal activity did not affect the preference. Our findings suggest that oligodendrocytes can selectively form myelin on particular groups of axons and modulate myelin structures at the cellular level depending on axonal activity driven by environmental stimuli. 7月7日（金）　10:40-12:40　Room E 2SY④-2 ユビキチン・プロテアソームシステム依存的タンパク質分解の破綻による行動変化の機序の解明 Mechanism of Behavioral Changes Caused by Disruption of Ubiquitin-Proteasome System-Dependent Protein Degradation 大野　萌馨1,2, 若月　修二1, 高尾　啓三3, 荒木　敏之1,2 1. 国立精神医療研究セ　神経研, 2. 東京農工大学　工学府　生命工学, 3. 富山大　学術研究部　医学系 Moeka Ohno1,2, Shuji Wakatsuki1, Keizou Takao3, Toshiyuki Araki1,2 1. Natl. Inst. Neurosci., NCNP, Japan, 2. Dept. Biotech & Life Sci., Grad Sch of Eng., Univ. of Agric & Eng, Japan, 3. Fac. Med., Univ. of Toyama, Japan Dysregulation of proteolytic systems has attracted attention as one of the molecular mechanisms of neurodevelopmental disorders. Some of the ubiquitin-proteasome system (UPS)-related genes have been identified as risk genes for the disorders. Zinc and Ring Finger1 (ZNRF1) is a ubiquitin ligase expressed in neurons throughout the nervous system during development and in adulthood. Previous works have shown that ZNRF1 induces axonal degeneration in response to stimuli causing neuronal damage, but its function during brain development is not clear. We aim to elucidate the role of UPS in the neural circuit formation during development by analyzing developmental abnormalities of ZNRF1 knockout (KO) mice. We found, by electrophysiological and morphological analyses, that ZNRF1 contributes to regulate subtype-specific expression of voltage-gated Na+ ion channels on the hippocampal neuron membrane. Comprehensive behavioral analysis of ZNRF1 KO mice revealed that they show decreased pre-pulse inhibition, hyperactivity and increased fearful behavior during fear test. These data suggest that ZNRF1 may be involved in fear memory formation and/or maintenance, which may be consistent with the previous reports showing the increased UPS function after fear conditioning. We will elucidate the molecular mechanisms that causes behavioral abnormalities under ZNRF1 deficiency in the future. 7月7日（金）　10:40-12:40　Room E 2SY④-3 組織損傷に応答してスイッチオンされる神経依存性創傷治癒 Implication of the neuron-specific metallopeptidase in nerve-dependent wound healing 桐生　寿美子, 木山　博資 名古屋大学　大学院医学系研究科　機能組織学 Sumiko Kiryu-Seo, Hiroshi Kiyama Dept Functional Anat & Neurosci, Nagoya Univ, Grad Sch Med, Nagoya, Japan Nerves are considered to play a crucial role for wound healing, which is delayed in neuropathy. However, it is not clear how nerves regulate this process. We here show that a membrane-bound neuronal metalloprotease, Damage-induced neuronal endopeptidase (DINE), is involved in nerve-dependent wound healing. DINE has been supposed to be responsible for degradation and/or processing of peptides, due to the structural similarity with Neprilysin, amyloid β degrading enzyme. The expression of DINE is highly up-regulated in response to various nerve injuries. Thus, neuronal DINE could have an important impact on the injured microenvironment through the cleaved peptides. Our established DINE-deficient mice often showed the corneal opacity and severe skin wound along with aging. It is probably due to the failure of nerve-dependent wound healing. Furthermore, the nerve injury-specific DINE deletion in mice delayed wound healing after tissue damage. DINE-deficient axonal tip after tissue damage showed the retraction-bulb like structure and disturbed local nerve regeneration in newly-generated tissue regions. Intriguingly, the DINE deficiency in injured axons altered the character of injury-specific fibroblast clusters in microenvironment, which might impair the local nerve regeneration and wound healing. Our findings would shed light on the new mechanisms of nerve-dependent tissue repair. 7月7日（金）　10:40-12:40　Room E 2SY④-4 神経変性疾患における軸索内mRNA輸送と翻訳制御の役割 Role of axonal mRNA transport and translational regulation in neurodegenerative diseases 長野　清一 大阪大学　神経難病認知症探索治療学 Seiichi Nagano Dept. of Neurotherapeutics, Osaka University, Suita, Japan In neurodegenerative diseases, abnormalities in RNA metabolism have been suggested to be associated with pathological conditions. In amyotrophic lateral sclerosis (ALS), in particular, altered localization and abnormal deposition of TDP-43 and other RNA-binding proteins in neurons have been reported, suggesting that changes in RNA expression, localization, and translation through these alterations may be closely related to pathogenesis.We considered the possibility that morphological characteristics of neurons may influence RNA metabolism to cause neurodegeneration, and searched for mRNAs transported to neuronal axons by TDP-43. We found that several ribosomal protein mRNAs are transported by TDP-43. These mRNAs are translated in the axon and the translated ribosomal proteins are assembled into ribosomes, where they play an important role in regulating local translational functions. This suggests that TDP-43 dysfunction in ALS results in impaired local translation in the axon, which contributes to neurodegeneration. Based on these results, we are currently developing a new treatment strategy for ALS by improving the function of ribosomes using viral vectors expressing ribosomal proteins.In this talk, I will review the significance of local translation dysfunction in ALS and other neurodegenerative diseases, including the data of our study. 7月7日（金）　10:40-12:40　Room E 2SY④-5 力を介した軸索ガイダンス機構とその破綻による病態 Mechanical regulation and pathology in axon guidance 稲垣　直之 奈良先端科学技術大学院大学 Naoyuki Inagaki Nara Institute of Science and Technology The generation of protrusive forces against microenvironments is essential to drive neural wiring processes, including neuronal migration, axon guidance, synapse formation and synaptic plasticity. A variety of extracellular signals, such as diffusible and nondiffusible axon guidance molecules, neurotransmitters, and environmental stiffness, regulate these processes. Axon guidance guided by diffusible and substrate-bound chemicals are called chemotaxis and haptotaxis, respectively. Environmental mechanical properties also regulate axon guidance, and cell movement guided by extracellular stiffness is referred to as durotaxis. We report that the clutch molecule shootin1 and cell adhesion molecule L1-CAM constitute a tunable molecular clutch system that transduces netrin-1-induced chemotactic signal, laminin-induced haptotactic signal and durotactic signal to the forces regulating axon outgrowth and guidance. This tunable clutch system also mediates neuronal migration, dendritic spine formation and structural synaptic plasticity. We further show that this mechanism is disrupted in a human patient with L1-CAM syndrome, suffering corpus callosum agenesis and corticospinal tract hypoplasia.