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論文 - 木下　専

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Septin 3 regulates memory and L-LTP-dependent extension of endoplasmic reticulum into spines 査読有り Open Access

Ageta-Ishihara N, Fukazawa Y, Arima-Yoshida F, Okuno H, Ishii Y, Takao K, Konno K, Fujishima K, Ageta H, Hioki H, Tsuchida K, Sato Y, Kengaku M, Watanabe M, Watabe AM, Manabe T, Miyakawa T, Inokuchi K, Bito H, and Kinoshita M

Cell Reports 44 巻 ( 3 ) 2025年2月

Expression analyses of Rich2/Arhgap44, a Rho family GTPase-activating protein, during mouse brain development. 査読有り

Goto N, Nishikawa M, Ito H, Noda M, Hamada N, Tabata H, Kinoshita M, Nagata K

Developmental Neuroscience 45 巻頁： 19 - 26 2023年1月

Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease 査読有り国際共著

Julia Viard, Yann Loe-Mie, Rachel Daudin, Malik Khelfaoui, Christine Plancon, Anne Boland, Francisco Tejedor, Richard L. Huganir, Eunjoon Kim, Makoto Kinoshita, Guofa Liu, Volker Haucke, Thomas Moncion, Eugene Yu, Valérie Hindie, Henri Bléhaut, Clotilde Mircher, Yann Herault, Jean-François Deleuze, Jean-Christophe Rain, Michel Simonneau, Aude-Marie Lepagnol-Bestel

Life Science Alliance 5 巻 ( 12 ) 頁： e202101205 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cold Spring Harbor Laboratory

<title>ABSTRACT</title>Intellectual disability (ID) found in Down syndrome (DS), which is characterized by an extra copy of 234 genes on Chr21 is poorly understood. We first used two DS mouse models that either display an extra copy of the <italic>Dyrk1A</italic> gene or of the mouse Chr16 syntenic region. Exome sequencing of transcripts deregulated in embryonic hippocampus uncovers enrichment in genes involved in chromatin and synapse respectively. Using large-scale yeast two-hybrid screen (154 distinct screens) of human brain library containing at least 10<sup>7</sup> independent fragments, we identified 3,636 novel protein-protein interactions with an enrichment of direct interactors of both Chromosome 21(Hsa21) baits and rebounds in ID-related genes. Using proximity ligation assays, we identified that Hsa21-encoded proteins are located at the dendritic spine postsynaptic density in a protein network located at the dendritic spine post synapse. Hsa21 DYRK1A and DSCAM that confers a ~ 20-fold increase in Autism Spectrum Disorders (ASDs) are part of this dendritic spine postsynaptic network. We found that a DSCAM intracellular domain binds either DYRK1A or DLGs that are multimeric scaffolds for the clustering of receptors, ion channels, and associated signaling proteins. The DYRK1A-DSCAM interaction is conserved from drosophila to humans. The identified postsynaptic.network is enriched in ARC-related synaptic plasticity, ASDs and Late-Onset Alzheimer Disease. Altogether, these results emphasize links between DS and brain diseases with complex genetics.

DOI： 10.26508/lsa.202101205

Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks 査読有り

Asada-Utsugi M., Uemura K., Kubota M., Noda Y., Tashiro Y., Uemura T. M., Yamakado H., Urushitani M., Takahashi R., Hattori S., Miyakawa T., Ageta-Ishihara N., Kobayashi K., Kinoshita M., Kinoshita A.

14 巻 ( 1 ) 2021年1月

Developmental and postdevelopmental roles of septins in the brain 招待有り査読有り国際誌

Neuroscience Research 2020年11月

PCP-dependent transcellular regulation of actomyosin oscillation facilitates convergent extension of vertebrate tissue 査読有り国際共著

Asako Shindo, Yasuhiro Inoue, Makoto Kinoshita, John B. Wallingford

Developmental Biology 446 巻 ( 2 ) 頁： 159 - 167 2019年2月

UBL3 modification influences protein sorting to small extracellular vesicles 査読有り

Hiroshi Ageta, Natsumi Ageta-Ishihara, Keisuke Hitachi, Ozge Karayel, Takanori Onouchi, Hisateru Yamaguchi, Tomoaki Kahyo, Ken Hatanaka, Koji Ikegami, Yusuke Yoshioka, Kenji Nakamura, Nobuyoshi Kosaka, Masashi Nakatani, Akiyoshi Uezumi, Tomihiko Ide, Yutaka Tsutsumi, Haruhiko Sugimura, Makoto Kinoshita, Takahiro Ochiya, Matthias Mann, Mitsutoshi Setou, Kunihiro Tsuchida

Nature Communications 9 巻 ( 1 ) 2018年12月

CDC42EP4, a perisynaptic scaffold protein in Bergmann glia, is required for glutamatergic tripartite synapse configuration. 招待有り査読有り国際誌

Natsumi Ageta-Ishihara, Kohtarou Konno, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Masahiko Watanabe, Makoto Kinoshita

Neurochemistry International 119 巻頁： 190 - 198 2018年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier {BV}

Configuration of tripartite synapses, comprising the pre-, post-, and peri-synaptic components (axon terminal or bouton, dendritic spine, and astroglial terminal process), is a critical determinant of neurotransmitter kinetics and hence synaptic transmission. However, little is known about molecular basis for the regulation of tripartite synapse morphology. Previous studies showed that CDC42EP4, an effector protein of a cell morphogenesis regulator CDC42, is expressed exclusively in Bergmann glia in the cerebellar cortex, that it forms tight complex with the septin heterooligomer, and that it interacts indirectly with the glutamate transporter GLAST and MYH10/nonmuscle myosin ΙΙB. Scrutiny of Cdc42ep4-/- mice had revealed that the CDC42EP4-septins-GLAST interaction facilitates glutamate clearance, while the role for CDC42EP4-septins-MYH10 interaction has remained unsolved. Here, we find anomalous configuration of the tripartite synapses comprising the parallel fiber boutons, dendritic spines of Purkinje cells, and Bergmann glial processes in Cdc42ep4-/- mice. The complex anomalies include 1) recession of Bergmann glial membranes from the nearest active zones, and 2) extension of nonactive synaptic contact around active zone. In line with the recession of Bergmann glial membranes by the loss of CDC42EP4, overexpression of CDC42EP4 in heterologous cells promotes cell spreading and partitioning of MYH10 to insoluble (i.e., active) fraction. Paradoxically, however, Cdc42ep4-/- cerebellum contained significantly more MYH10 and N-cadherin, which is attributed to secondary neuronal response mainly in Purkinje cells. Given cooperative actions of N-cadherin and MYH10 for adhesion between neurons, we speculate that their augmentation may reflect the extension of nonactive synaptic contacts in Cdc42ep4-/- cerebellum. Transcellular mechanism that links the absence of CDC42EP4 in Bergmann glia to the augmentation of N-cadherin and MYH10 in neurons is currently unknown, but the phenotypic similarity to GLAST-null mice indicates involvement of the glutamate intolerance. Together, the unique phenotype of Cdc42ep4-/- mice provides a clue to novel molecular network underlying tripartite synapse configuration.

DOI： 10.1016/j.neuint.2018.01.003

Web of Science

PubMed

Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing. 査読有り国際共著国際誌

Asako Shindo, Anastasia Audrey, Maki Takagishi, Masahide Takahashi, John B Wallingford, Makoto Kinoshita

Journal of Cell Science 131 巻 ( 12 ) 頁： jcs212647 - jcs212647 2018年6月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：The Company of Biologists

Wounds in embryos heal rapidly through contraction of the wound edges. Despite well-recognized significance of the actomyosin purse string for wound closure, roles for other cytoskeletal components are largely unknown. Here, we report that the septin cytoskeleton cooperates with actomyosin and microtubules to coordinate circumferential contraction of the wound margin and concentric elongation of wound-proximal cells in Xenopus laevis embryos. Microtubules reoriented radially, forming bundles along lateral cell cortices in elongating wound-proximal cells. Depletion of septin 7 (Sept7) slowed wound closure by attenuating the wound edge contraction and cell elongation. ROCK/Rho-kinase inhibitor-mediated suppression of actomyosin contractility enhanced the Sept7 phenotype, whereas the Sept7 depletion did not affect the accumulation of actomyosin at the wound edge. The cortical microtubule bundles were reduced in wound-proximal cells in Sept7 knockdown (Sept7-KD) embryos, but forced bundling of microtubules mediated by the microtubule-stabilizing protein Map7 did not rescue the Sept7-KD phenotype. Nocodazole-mediated microtubule depolymerization enhanced the Sept7-KD phenotype, suggesting that Sept7 is required for microtubule reorganization during cell elongation. Our findings indicate that septins are required for the rapid wound closure by facilitating cortical microtubule reorganization and the concentric elongation of surrounding cells.

DOI： 10.1242/jcs.212647

Web of Science

PubMed

神経ネットワークの形と機能を制御する細胞骨格系分子群招待有り

木下　専

DOJIN BIOSCIENCE SERIES 28脳神経化学　脳はいま化学の言葉でどこまで語れるか 2018年4月

グルタミン酸輸送体の足場となり、クリアランスを促進するシナプス周囲グリア突起内の蛋白質複合体招待有り

木下　専

日本生物学的精神医学会誌（特集　精神神経疾患と興奮性アミノ酸受容体） 28 巻 ( 2 ) 頁： 84 - 86 2017年4月

Septin Interferes with the Temperature-Dependent Domain Formation and Disappearance of Lipid Bilayer Membranes. 査読有り国際誌

Shunsuke Yamada, Takumi Isogai, Ryugo Tero, Yohko Tanaka-Takiguchi, Toru Ujihara, Makoto Kinoshita, Kingo Takiguchi

Langmuir : the ACS journal of surfaces and colloids 32 巻 ( 48 ) 頁： 12823 - 12832 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Chemical Society ({ACS})

Domain formation or compartmentalization in a lipid bilayer membrane has been thought to take place dynamically in cell membranes and play important roles in the spatiotemporal regulation of their physiological functions. In addition, the membrane skeleton, which is a protein assembly beneath the cell membrane, also regulates the properties as well as the morphology of membranes because of its role as a diffusion barrier against constitutive molecules of the membrane or as a scaffold for physiological reactions. Therefore, it is important to study the relationship between lipid bilayer membranes and proteins that form the membrane skeleton. Among cytoskeletal systems, septin is unique because it forms arrays on liposomes that contain phosphoinositides, and this property is thought to contribute to the formation of the annulus in sperm flagellum. In this study, a supported lipid bilayer (SLB) was used to investigate the effect of septin on lipid bilayers because SLBs rather than liposomes are suitable for observation of the membrane domains formed. We found that SLBs containing phosphatidylinositol (PI) reversibly form domains by decreasing the temperature and that septin affects both the formation and the disappearance of the cooling-induced domain. Septin inhibits the growth of cooling-induced domains during decreases in temperature and inhibits the dispersion and the disappearance of those domains during increases in temperature. These results indicate that septin complexes, i.e., filaments or oligomers assembling on the surface of lipid bilayer membranes, can regulate the dynamics of domain formation via their behavior as an anchor for PI molecules.

DOI： 10.1021/acs.langmuir.6b03452

Web of Science

PubMed

Septin7 regulates inner ear formation at an early developmental stage. 査読有り国際誌

Hiroko Torii, Atsuhiro Yoshida, Tatsuya Katsuno, Takayuki Nakagawa, Juichi Ito, Koichi Omori, Makoto Kinoshita, Norio Yamamoto

Developmental biology 419 巻 ( 2 ) 頁： 217 - 228 2016年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Septins are guanosine triphosphate-binding proteins that are evolutionally conserved in all eukaryotes other than plants. They function as multimeric complexes that interact with membrane lipids, actomyosin, and microtubules. Based on these interactions, septins play essential roles in the morphogenesis and physiological functions of many mammalian cell types including the regulation of microtubule stability, vesicle trafficking, cortical rigidity, planar cell polarity, and apoptosis. The inner ear, which perceives auditory and equilibrium sensation with highly differentiated hair cells, has a complicated gross morphology. Furthermore, its development including morphogenesis is dependent on various molecular mechanisms, such as apoptosis, convergent extension, and cell fate determination. To determine the roles of septins in the development of the inner ear, we specifically deleted Septin7 (Sept7), the non-redundant subunit in the canonical septin complex, in the inner ear at different times during development. Foxg1Cre-mediated deletion of Sept7, which achieved the complete knockout of Sept7 within the inner ear at E9.5, caused cystic malformation of inner ears and a reduced numbers of sensory epithelial cells despite the existence of mature hair cells. Excessive apoptosis was observed at E10.5,E11.5 and E12.5 in all inner ear epithelial cells and at E10.5 and E11.5 in prosensory epithelial cells of the inner ears of Foxg1Cre;Septin7floxed/floxed mice. In contrast with apoptosis, cell proliferation in the inner ear did not significantly change between control and mutant mice. Deletion of Sept7 within the cochlea at a later stage (around E15.5) with Emx2Cre did not result in any apparent morphological anomalies observed in Foxg1Cre;Septin7floxed/floxed mice. These results suggest that SEPT7 regulates gross morphogenesis of the inner ear and maintains the size of the inner ear sensory epithelial area and exerts its effects at an early developmental stage of the inner ear.

DOI： 10.1016/j.ydbio.2016.09.012

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PubMed

A septin requirement differentiates autonomous and contact-facilitated T cell proliferation. 査読有り国際共著国際誌

Adriana M Mujal, Julia K Gilden, Audrey Gérard, Makoto Kinoshita, Matthew F Krummel

Nature Immunology 17 巻 ( 3 ) 頁： 315 - 22 2016年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Nature

T cell proliferation is initiated by T cell antigen receptor (TCR) triggering, soluble growth factors or both. In characterizing T cells lacking the septin cytoskeleton, we found that successful cell division has discrete septin-dependent and septin-independent pathways. Septin-deficient T cells failed to complete cytokinesis when prompted by pharmacological activation or cytokines. In contrast, cell division was not dependent on septins when cell-cell contacts, such as those with antigen-presenting cells, provided a niche. This septin-independent pathway was mediated by phosphatidylinositol-3-OH kinase activation through a combination of integrins and costimulatory signals. We were able to differentiate between cytokine- and antigen-driven expansion in vivo and thus show that targeting septins has strong potential to moderate detrimental bystander or homeostatic cytokine-driven proliferation without influencing expansion driven by conventional antigen-presentation.

DOI： 10.1038/ni.3330

Web of Science

PubMed

Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization 査読有り

Horigane S, Ageta-Ishihara N, Fujii H, Kinoshita M, Takemoto-Kimura S, Bito H

Molecular Brain 9 巻 ( 8 ) 2016年1月

Methods for immunoblot detection and electron microscopic localization of septin subunits in mammalian nervous systems 招待有り

L. K. Parajuli, N. Ageta-Ishihara, H. Ageta, Y. Fukazawa, M. Kinoshita

Methods in Cell Biology 136 巻頁： 285 - 294 2016年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：ELSEVIER ACADEMIC PRESS INC

The minimal functional units of the mammalian septin system are diverse heterooligomers of SEPT1 1-14 subunits, which are most abundantly and differentially expressed in post mitotic neurons and glia. The subunit compositions of such heterooligomers are thought to differentiate their affinity for other proteins and lipids, and subcellular localization. Thus, high-precision quantification and mapping of each subunit is necessary to understand their subcellular functions and physiological roles. However, systematic information on the localization of individual septin subunits in the mammalian nervous system is limited. Here, we present our experimental workflows for the study of septin expression and localization in the rodent brain by immunoblot and serial section immunoelectron microscopy. Our protocols, based on standard methods, have been rigorously optimized and simplified for universality and reproducibility to aid non-experts in the field.

DOI： 10.1016/bs.mcb.2016.04.021

Web of Science

CDC42EP4/BORG4-septin complex beneath perisynaptic membrane domains of Bergmann glial processes facilitates GLAST-mediated glutamate clearance and motor learning.

Ageta-Ishihara N., Kinoshita M.

Molecular Biology of the Cell 27 巻 2016年

A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. 査読有り国際共著国際誌

Natsumi Ageta-Ishihara, Maya Yamazaki, Kohtarou Konno, Hisako Nakayama, Manabu Abe, Kenji Hashimoto, Tomoki Nishioka, Kozo Kaibuchi, Satoko Hattori, Tsuyoshi Miyakawa, Kohichi Tanaka, Fathul Huda, Hirokazu Hirai, Kouichi Hashimoto, Masahiko Watanabe, Kenji Sakimura, Makoto Kinoshita

Nature Communications 6 巻 ( 10090 ) 頁： 10090 - 10090 2015年12月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Nature

The small GTPase-effector proteins CDC42EP1-5/BORG1-5 interact reciprocally with CDC42 or the septin cytoskeleton. Here we show that, in the cerebellum, CDC42EP4 is exclusively expressed in Bergmann glia and localizes beneath specific membrane domains enwrapping dendritic spines of Purkinje cells. CDC42EP4 forms complexes with septin hetero-oligomers, which interact with a subset of glutamate transporter GLAST/EAAT1. In Cdc42ep4(-/-) mice, GLAST is dissociated from septins and is delocalized away from the parallel fibre-Purkinje cell synapses. The excitatory postsynaptic current exhibits a protracted decay time constant, reduced sensitivity to a competitive inhibitor of the AMPA-type glutamate receptors (γDGG) and excessive baseline inward current in response to a subthreshold dose of a nonselective inhibitor of the glutamate transporters/EAAT1-5 (DL-TBOA). Insufficient glutamate-buffering/clearance capacity in these mice manifests as motor coordination/learning defects, which are aggravated with subthreshold DL-TBOA. We propose that the CDC42EP4/septin-based glial scaffold facilitates perisynaptic localization of GLAST and optimizes the efficiency of glutamate-buffering and clearance.

DOI： 10.1038/ncomms10090

Web of Science

PubMed

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism 査読有り

Kitao Y, Ageta-Ishihara N, Takahashi R, *Kinoshita M, *Hori O.

F1000 Research 4 巻 ( 130 ) 頁： - 2015年5月

SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow 査読有り国際共著国際誌

Yorito Hattori, Yoko Okamoto, Kazuyuki Nagatsuka, Ryosuke Takahashi, Rajesh N. Kalaria, Makoto Kinoshita, Masafumi Ihara

NeuroReport 26 巻 ( 3 ) 頁： 113 - 117 2015年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

Silent information regulator 2 homolog 1 (SIRT1) is a protein deacetylase that has been reported to suppress neurodegenerative and cardiovascular pathologies in model organisms. We have recently reported that SIRT1 overexpression preserves cerebral blood flow (CBF) after bilateral common carotid artery stenosis (∼50% stenosis) by the deacetylation of endothelial nitric oxide synthase. This study was designed to determine whether cerebral SIRT1 expression would be effective in a more severe model of cerebral ischemia caused by bilateral common carotid artery occlusion (BCAO) in vivo. Sirt1-overexpressing (Sirt1-Tg) mice (n=13) and their wild-type littermates (n=17) were subjected to BCAO for 10 min using microaneurysm clips. Temporal CBF changes were measured by laser speckle flowmetry before and 5, 10 min, and 2 h after BCAO. Histological evaluation of hippocampal changes was performed 7 days after BCAO. Histological findings were significantly less severe in Sirt1-Tg mice than in wild-type mice; wild-type mice showed strokes in the hippocampus, whereas Sirt1-Tg mice had minimal hippocampal damage 7 days after BCAO. Consistent with this observation, wild-type mice showed a severe reduction in CBF to ∼20-25% of the baseline level during BCAO, whereas Sirt1-Tg littermates showed significantly preserved CBF up to 45-50% of the baseline level. Our study provides evidence for the promising role of SIRT1 in protecting against cerebral global ischemia by preserving CBF and restoring the cerebrovascular reserve.

DOI： 10.1097/WNR.0000000000000308

Web of Science

PubMed

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