若手道場
グリア機能と疾患 |
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| 7月6日（木） 15:20-16:20 Room D
1W⑤-1
RNAヘリカーゼDdx20欠損によるタモキシフェン誘導性脱髄モデルマウスの表現型解析
Analysis of a tamoxifen-inducible demyelinating mouse model with the deficiency of RNA helicase Ddx20
伊勢 正崇, 備前 典久, シマンコワ アンナ, 竹林 浩秀
新潟大学大学院医歯学総合研究科 脳機能形態学分野
Masataka Ise, Norihisa Bizen, Anna Simankova, Hirohide Takebayashi
Division of Neurobiology and Anatomy Graduate School of Medical and Dental Sciences Niigata University
Oligodendrocytes generate myelin sheaths for the formation, health, and function of the central nervous system. The loss of myelin sheath leads to demyelinating diseases such as multiple sclerosis, which has trouble with neuronal signal transduction. We have demonstrated that RNA helicase Ddx20 (DEAD box protein 20), which has been known to play a role in the assembly of small nuclear ribonucleoprotein (snRNP) and transcriptional regulation, is indispensable for the oligodendrocyte development, differentiation, and maturation in the central nervous system (Bizen et al., 2022; Simankova et al., 2021). To elucidate the role of Ddx20 in mature oligodendrocytes, we generated the Ddx20 inducible knockout (KO) mice (Plp-CreER; Ddx20fl/fl) in the mature oligodendrocyte-specific manner. Immunohistochemistry and in situ hybridization showed that Ddx20 ablation induced loss of mature oligodendrocytes, and accumulation of activated microglia by 4 weeks after tamoxifen injection. By 4.5 weeks, we found the rapid loss of neurons and the regeneration of mature oligodendrocytes in the gray matter of the spinal cord. These results suggest that the Ddx20 inducible KO mice could be a novel demyelinating mouse model and useful to investigate the activated microglia in the process of acute demyelination. | | 7月6日（木） 15:20-16:20 Room D
1W⑤-2
軸索切断したラットの顔面神経核におけるシグナル分子の変動
Changes of signaling molecules in the axotomized rat facial nucleus
石嶋 貴志1, 中嶋 一行1,2
1. 創価大学大学院 理工学研究科生命理学専攻, 2. 創価大学糖鎖生命システム融合研究所
Takashi Ishijima1, Kazuyuki Nakajima1,2
1. Dept. of Life science, Graduate school of Science and Engineering, Soka university, Tokyo, Japan, 2. Glycan & Life Systems Integration Center (GaLSIC) Soka university, Tokyo, Japan.
Axotomy of the rat facial nerve causes functional downregulation of injured motoneurons, and microglial proliferation. These cellular responses are thought to be related to the survival, repair and regeneration of motoneurons. However, it is still unclear which signaling molecules are involved in these responses. In this study, we investigated the changes and localizations of several signaling molecules, including c-Jun, c-Fos, CREB, ATF2, extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38. These molecules were analyzed by immunoblotting and immunohistochemistry. The level of c-Jun was increased in injured motoneurons, but the level of p-CREB was significantly decreased in injured motoneurons. p-CREB/CREB and ATF2 were immunohistochemically increased in microglia. The levels of p-ERK1/2 and p-JNK1 were decreased in injured motoneurons. The levels of p-p38 and p38 were increased in microglia. In vitro experiments revealed that p38 and CREB were activated in proliferating microglia. These results suggested that c-Jun is involved in the survival, repair and regeneration of motoneurons, but p-CREB, p-ERK1/2 and p-JNK are associated with the functional downregulation of motoneurons. On the other hand, p-p38/p38 and p-CREB/CREB were suggested to be involved in the activation/proliferation of microglia. | | 7月6日（木） 15:20-16:20 Room D
1W⑤-3
エンリッチ環境飼育はM2ミクログリアへの誘導と神経新生を促進し、慢性予測不能軽度ストレス負荷によるうつ様行動を緩解する
Enriched environments differentiate into M2 microglia, promote neurogenesis and ameliorate depression-like behavior
長谷川 眞也1, 毛利 彰宏1,4, 國澤 和生1, 坂田 昴駿1, 吉田 有美香1, 中原 伽梨1, 倉橋 仁美1, 齋藤 邦明2,3,4, 鍋島 俊隆3,4
1. 藤田医科大学 大学院保健学研究科 レギュラトリーサイエンス分野, 2. 藤田医科大学 大学院保健学研究科 先進診断システム開発分野, 3. 藤田医科大学 大学院保健学研究科 健康医科学創造共同研究部門, 4. NPO法人医薬品適正使用推進機構
Masaya Hasegawa1, Akihiro Mouri1,4, Kazuo Kunisawa1, Takatoshi Sakata1, Yumika Yoshida1, Karin Nakahara1, Hitomi Kurahashi1, Kniaki Saito2,3,4, Toshitaka Nabeshima3,4
1. Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.
Chronic stress is a risk factor for the major depressive disorder (MDD) and disruption of neurogenesis is suggested to be involved in the pathophysiology of MDD. Enriched environments (EE) promote neurogenesis and produce resistance against neuronal toxicity. Therefore, we investigated whether EE ameliorate chronic unpredictable mild stress (CUMS)-induced disruption of neurogenesis and depression-like behavior. EE attenuated the CUMS-induced abnormal behaviors in social interaction test, novelty suppressed feeding test, and tail suspension test. Furthermore, EE attenuated the CUMS-induced decrease of neurogenesis and neuronal survival in the dentate gyrus of hippocampus (HIP). EE suppressed the CUMS-induced decrease in mRNA levels of tumor necrosis factor-α (TNF-α), M1 microglia marker, and Iba1, microglia marker, in the HIP immediately after CUMS. On the contrary, one week after CUMS, EE attenuated the CUMS-induced increase in mRNA levels of TNF-α, while it increased mRNA levels of M2 microglia markers such as CD206, Ym1, and transforming growth factor-β (TGF-β) in the HIP. These data suggested that EE protected microglial decline by CUMS and subsequently promoted M2 microglial differentiation. In conclusion, EE ameliorated the CUMS-induced depression-like behavior and the disruption of hippocampal neurogenesis through the promotion of M2 microglial differentiation. | | 7月6日（木） 15:20-16:20 Room D
1W⑤-4
A new approach to characterization of glioblastoma multiforme
岡野 雄士, 加瀬 義高, 岡野 栄之
慶應義塾大学 医学部 生理学教室
Yuji Okano, Yoshitaka Kase, Hideyuki Okano
Dept. of Physiol., Keio Univ. Sch. of Med, Tokyo, Japan
Glioblastoma multiforme (GBM) is one of the most frequent and fatal primary malignant brain tumors which is known to show strong resistance to conventional therapy. Its clinical challenges come from its heterogeneity in genotypes and phenotypes.Several studies have already reported GBM biomarkers using single-cell RNA sequencing(scRNA-seq) to better understand this disease. Although they have proposed candidategenes to characterize GBM cells, a necessary and sufficient gene to fully explain their general character is yet to be discovered.In this study, to capture GBM's universality, we tried to characterize GBM using multiple genes found in normal brain cells rather than finding a single gene that is exceptionally positive in GBM cells. Using multiple scRNA-seq datasets of normal cells in the central nervous system (CNS) and GBM cells, we found that GBM cells have unique and preserved expression patterns of four specific genes out of 55 CNS-marker genes.Furthermore, we denoted an algorithm to classify GBM cells by logical operations as adiagram inspired by an electrical circuit. We confirmed that we could filter GBM cells by sequential logical operations based on the genes’ expression patterns. | |
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