Updated on 2024/03/04

写真a

 
NISHIKAWA Masashi
 
Organization
Graduate School of Science Assistant Professor
Graduate School
Graduate School of Science
Undergraduate School
School of Science Department of Biological Science
Title
Assistant Professor

Research Interests 7

  1. G protein

  2. cell signaling pathway

  3. Molecular biology

  4. In utero electroporation

  5. Neurodevelopmental disorders

  6. Neurodevelopment

  7. cytoskeleton

Research Areas 5

  1. Life Science / Molecular biology

  2. Life Science / Developmental biology

  3. Life Science / Anatomy and histopathology of nervous system

  4. Life Science / Neuroscience-general

  5. Life Science / Cell biology

Research History 2

  1. Nagoya University   Division of Biological Sciences, Nagoya University Graduate School of Science, Nagoya   Assistant Professor

    2022.6

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    Country:Japan

  2. Institute for Developmental Research, Aichi Developmental Disability Center   Department of Molecular Neurobiology   Research resident

    2020.4 - 2022.5

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    Country:Japan

Professional Memberships 4

  1. 日本臨床分子形態学会

    2020

  2. 日本神経化学会

    2020

  3. 日本生化学会

    2016

  4. 日本分子生物学会

    2016

Committee Memberships 2

  1. 日本臨床分子形態学会   評議員  

    2023.4 - 2026.3   

  2. 日本臨床分子形態学会   第53回日本臨床分子形態学会総会・学術集会 実行委員  

    2021.10   

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    Committee type:Academic society

Awards 3

  1. The Award for Young Investigator of Japanese Society for Neurochemistry

    2023   The Japanese Society for Neurochemistry   Pathophysiological mechanisms underlying neurodevelopmental disorders caused by Rac GTPases dysregulation

    Masashi Nishikawa

  2. 奨励賞

    2022.5   日本生化学会中部支部  

    西川将司, 伊東秀記, 田畑 秀典, 永田浩一

  3. Best Presentation Award of The Japanese Society for Neurochemistry

    2021.10   The Japanese Society for Neurochemistry   Pathophysiological significance of RAC3 variants in neurodevelopmental disorders

 

Papers 16

  1. A Novel Constitutively Active c:98G > C, p.(R33P) Variant in RAB11A Associated with Intellectual Disability Promotes Neuritogenesis and Affects Oligodendroglial Arborization Reviewed

    Yumi Tsuneura, Taeko Kawai, Keitaro Yamada, Shintaro Aoki, Mitsuko Nakashima, Shima Eda, Tohru Matsuki, Masashi Nishikawa, Koh-ichi Nagata, Yasushi Enokido, Hirotomo Saitsu, Atsuo Nakayama

    Human Mutation   Vol. 2023   page: 1 - 12   2023.8

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    Publishing type:Research paper (scientific journal)   Publisher:Hindawi Limited  

    Whole exome sequencing/whole genome sequencing has accelerated the identification of novel genes associated with intellectual disabilities (ID), and RAB11A which encodes an endosomal small GTPase is among them. However, consequent neural abnormalities have not been studied, and pathophysiological mechanisms underlying the ID and other clinical features in patients harboring RAB11A variants remain to be clarified. In this study, we report a novel de novo missense variant in RAB11A, NM_004663.5: c.98G>C, which would result in NP_004654.1: p.(R33P) substitution, in a Japanese boy with severe ID and hypomyelination. Biochemical analyses indicated that the RAB11A-R33P is a gain-of-function, constitutively active variant. Accordingly, the introduction of the RAB11A-R33P promoted neurite extension in neurons like a known constitutively active variant Rab11A-Q70L. In addition, the RAB11A-R33P induced excessive branching with thinner processes in oligodendrocytes. These results indicate that the gain-of-function RAB11A-R33P variant in association with ID and hypomyelination affects neural cells and can be deleterious to them, especially to oligodendrocytes, and strongly suggest the pathogenic role of the RAB11A-R33P variant in neurodevelopmental impairments, especially in the hypomyelination.

    DOI: 10.1155/2023/8126544

    Other Link: http://downloads.hindawi.com/journals/humu/2023/8126544.xml

  2. Expression analyses of WAC, a responsible gene for neurodevelopmental disorders, during mouse brain development Reviewed

    Masashi Nishikawa, Tohru Matsuki, Nanako Hamada, Atsuo Nakayama, Hidenori Ito, Koh-ichi Nagata

    Medical Molecular Morphology     2023.7

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    Authorship:Lead author   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1007/s00795-023-00364-x

    Other Link: https://link.springer.com/article/10.1007/s00795-023-00364-x/fulltext.html

  3. A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association Reviewed

    Rie Seyama, Masashi Nishikawa, Yuri Uchiyama, Keisuke Hamada, Yuka Yamamoto, Masahiro Takeda, Takanori Ochi, Monami Kishi, Toshifumi Suzuki, Kohei Hamanaka, Atsushi Fujita, Naomi Tsuchida, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Shintaro Makino, Takashi Yao, Hidenori Ito, Atsuo Itakura, Kazuhiro Ogata, Koh-ichi Nagata, Naomichi Matsumoto

    Scientific Reports   Vol. 13 ( 1 )   2023.6

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    Authorship:Lead author   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T > C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.

    DOI: 10.1038/s41598-023-36381-0

    Other Link: https://www.nature.com/articles/s41598-023-36381-0

  4. Gain-of-function p.F28S variant in RAC3 disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder. Reviewed International journal

    Masashi Nishikawa, Marcello Scala, Muhammad Umair, Hidenori Ito, Ahmed Waqas, Pasquale Striano, Federico Zara, Gregory Costain, Valeria Capra, Koh-ichi Nagata

    Journal of medical genetics   Vol. 60 ( 3 ) page: 223 - 232   2023.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMJ  

    Background

    RAC3 encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants in RAC3 can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.

    Methods

    We investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) in RAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.

    Results

    In vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.

    Conclusion

    Our results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.

    DOI: 10.1136/jmedgenet-2022-108483

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  5. Expression Analyses of Rich2/Arhgap44, a Rho Family GTPase-Activating Protein, during Mouse Brain Development Reviewed

    Naoki Goto, Masashi Nishikawa, Hidenori Ito, Mariko Noda, Nanako Hamada, Hidenori Tabata, Makoto Kinoshita, Koh-ichi Nagata

    Developmental Neuroscience   Vol. 45 ( 1 ) page: 19 - 26   2023.1

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    Authorship:Lead author   Publishing type:Research paper (scientific journal)   Publisher:S. Karger AG  

    Rho family small GTPases, such as Rho, Rac, and Cdc42, play essential roles during brain development, by regulating cellular signaling and actin cytoskeletal reorganization. Rich2/Arhgap44, a Rac- and Cdc42-specific GTPase-activating protein, has been reported to be a key regulator for dendritic spine morphology and synaptic function. Given the essential roles of Rac and Cdc42 in brain development, Rich2 is supposed to take part in brain development. However, not only the molecular mechanism involved but also the expression profile of Rich2 during neurodevelopment has not yet been elucidated. In this study, we carried out expression analyses of Rich2 by focusing on mouse brain development. In immunoblotting, Rich2 exhibited a tissue-dependent expression profile in the young adult mouse, and the expression was increased during brain development. In immunohistochemical analyses, Rich2 was observed in the cytoplasm of cortical neurons at postnatal day (P) 0 and then came to be enriched in the nucleus with moderate distribution in neuropils at P7. Later at P30, a complex immunostaining pattern of Rich2 was observed; Rich2 was distributed in the nucleus, cytoplasm, and neuropils in many cortical neurons, whereas other neurons frequently displayed little expression. In the hippocampus at P7, Rich2 was distributed mainly in the cytoplasm of excitatory neurons in the cornu ammonis regions, while it was moderately detected in the nucleus in the dentate granule cells. Notably, Rich2 was distributed in excitatory synapses of the cornu ammonis 1 region at P30. Biochemical fractionation analyses also detected Rich2 in the postsynaptic density. Taken together, Rich2 is found to be expressed in the central nervous system in a developmental stage-dependent manner and may be involved in synapse formation/maintenance in cortical neurons.

    DOI: 10.1159/000529051

    PubMed

  6. Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex Reviewed

    Hidenori Tabata, Megumi Sasaki, Masakazu Agetsuma, Hitomi Sano, Yuki Hirota, Michio Miyajima, Kanehiro Hayashi, Takao Honda, Masashi Nishikawa, Yutaka Inaguma, Hidenori Ito, Hirohide Takebayashi, Masatsugu Ema, Kazuhiro Ikenaka, Junichi Nabekura, Koh-ichi Nagata, Kazunori Nakajima

    Nature Communications   Vol. 13 ( 1 )   2022.11

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Astrocytes are one of the most abundant cell types in the mammalian brain. They play essential roles in synapse formation, maturation, and elimination. However, how astrocytes migrate into the gray matter to accomplish these processes is poorly understood. Here, we show that, by combinational analyses of in vitro and in vivo time-lapse observations and lineage traces, astrocyte progenitors move rapidly and irregularly within the developing cortex, which we call erratic migration. Astrocyte progenitors also adopt blood vessel-guided migration. These highly motile progenitors are generated in the restricted prenatal stages and differentiate into protoplasmic astrocytes in the gray matter, whereas postnatally generated progenitors do not move extensively and differentiate into fibrous astrocytes in the white matter. We found Cxcr4/7, and integrin β1 regulate the blood vessel-guided migration, and their functional blocking disrupts their positioning. This study provides insight into astrocyte development and may contribute to understanding the pathogenesis caused by their defects.

    DOI: 10.1038/s41467-022-34184-x

    Other Link: https://www.nature.com/articles/s41467-022-34184-x

  7. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes Reviewed

    Marcello Scala, Masashi Nishikawa, Hidenori Ito, Hidenori Tabata, Tayyaba Khan, Andrea Accogli, Laura Davids, Anna Ruiz, Pietro Chiurazzi, Gabriella Cericola, Björn Schulte, Kristin G Monaghan, Amber Begtrup, Annalaura Torella, Michele Pinelli, Anne Sophie Denommé-Pichon, Antonio Vitobello, Caroline Racine, Maria Margherita Mancardi, Courtney Kiss, Andrea Guerin, Wendy Wu, Elisabeth Gabau Vila, Bryan C Mak, Julian A Martinez-Agosto, Michael B Gorin, Bugrahan Duz, Yavuz Bayram, Claudia M B Carvalho, Jaime E Vengoechea, David Chitayat, Tiong Yang Tan, Bert Callewaert, Bernd Kruse, Lynne M Bird, Laurence Faivre, Marcella Zollino, Saskia Biskup, Gabrielle Brown, Manish J Butte, Esteban C Dell'Angelica, Naghmeh Dorrani, Emilie D Douine, Brent L Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K Loo, Bryan C Mak, Martin G Martin, Julian A Martínez-Agosto, Elisabeth McGee, Stanley F Nelson, Shirley Nieves-Rodriguez, Christina G S Palmer, Jeanette C Papp, Neil H Parker, Genecee Renteria, Janet S Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Vincenzo Nigro, Nicola Brunetti-Pierri, Giorgio Casari, Gerarda Cappuccio, Annalaura Torella, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Pasquale Striano, Vincenzo Nigro, Mariasavina Severino, Valeria Capra, Gregory Costain, Koh-ichi Nagata

    Brain   Vol. 145 ( 9 ) page: 3308 - 3327   2022.9

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Abstract

    Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism.

    We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1.

    Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.

    DOI: 10.1093/brain/awac106

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    Other Link: https://academic.oup.com/brain/article-pdf/145/9/3308/45872573/awac106.pdf

  8. Expression Analyses of Polo-Like Kinase 4, a Gene Product Responsible for Autosomal Recessive Microcephaly and Seckel Syndrome, during Mouse Brain Development Reviewed

    Nanako Hamada, Ikuko Iwamoto, Mariko Noda, Masashi Nishikawa, Koh-ichi Nagata

    Developmental Neuroscience   Vol. 44 ( 6 ) page: 643 - 650   2022.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:S. Karger AG  

    Polo-like kinase 4 (Plk4) is a ser/thr kinase, which plays a central role in centriole duplication during the cell cycle. PLK4 gene abnormalities are responsible for autosomal recessive chorioretinopathy-microcephaly syndrome and Seckel syndrome. In this study, we performed expression analyses of Plk4 by focusing on mouse brain development. Western blotting analyses revealed that Plk4 with a molecular mass of ∼100 kDa was broadly expressed in adult mouse tissues with specific subcellular distribution. As to the central nervous system, Plk4 was expressed throughout the developmental process with drastic increase after P15, suggesting an essential role of Plk4 in differentiated neurons. In immunohistochemical analyses with mouse brain at embryonic day 14, Plk4 was detected dominantly at the cell-cell contact sites of neuronal progenitors in the ventricular zone. Plk4 was then diffusely distributed in the cell body of cortical neurons at P7, while it was enriched in the neuropil as well as soma of excitatory neurons in the cerebral cortex and hippocampus and Purkinje cells in the cerebellum at P30. Notably, biochemical fractionation analysis found an enrichment of Plk4 in the postsynaptic density fraction. Then, immunofluorescent analyses showed partial co-localization of Plk4 with excitatory synaptic markers, PSD95 and synaptophysin, in differentiated primary cultured hippocampal neurons. These results suggest that Plk4 takes part in the regulation of synaptic function in differentiated neurons.

    DOI: 10.1159/000526914

    PubMed

  9. Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes. Reviewed International journal

    Masashi Nishikawa, Hidenori Ito, Hidenori Tabata, Hiroshi Ueda, Koh-ichi Nagata

    Cells   Vol. 11 ( 4 ) page: 696 - 696   2022.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.

    DOI: 10.3390/cells11040696

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  10. Expression Analyses of Rac3, a Rho Family Small GTPase, during Mouse Brain Development. Reviewed International journal

    Masashi Nishikawa, Hidenori Ito, Mariko Noda, Nanako Hamada, Hidenori Tabata, Koh-ichi Nagata

    Developmental neuroscience   Vol. 44 ( 1 ) page: 49 - 58   2022.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:S. Karger AG  

    Rac3 is a member of Rho family small GTPases which regulate cellular signaling and cytoskeletal dynamics. The RAC3 gene abnormalities have been shown to cause neurodevelopmental disorders with structural brain anomalies, including polymicrogyria/dysgyria, callosal abnormalities, brainstem anomalies, and cerebellar dysplasia. Although this evidence indicates that Rac3 is essential in brain development, not only its molecular mechanism but also the expression profile is yet to be elucidated. In this study, we carried out expression analyses of Rac3 with mouse brain tissues. In immunoblotting, Rac3 exhibited a tissue-dependent expression profile in the young adult mouse and was expressed in a developmental stage-dependent manner in brain. In primary cultured hippocampal neurons, while Rac3 was distributed mainly in the cytoplasm, it was visualized in axon and dendrites with partial localization at synapses, in consistent with the observation in biochemical fractionation analyses. In immunofluorescence analyses with brain slices, Rac3 was distributed strongly and moderately in the axon and cytoplasm, respectively, of cerebral cortex at postnatal day (P) 2 and P18. Similar distribution profile was also observed in hippocampus. Taken together, the results obtained strongly suggest that Rac3 plays an important physiological role in neuronal tissues during corticogenesis, and defects in the Rac3 function induce structural brain anomalies leading to pathogenesis of neurodevelopmental disorders.

    DOI: 10.1159/000521168

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  11. The Rho guanine nucleotide exchange factor PLEKHG1 is activated by interaction with and phosphorylation by Src family kinase member FYN Reviewed

    Shun Nakano, Masashi Nishikawa, Tomoyo Kobayashi, Eka Wahyuni Harlin, Takuya Ito, Katsuya Sato, Tsuyoshi Sugiyama, Hisashi Yamakawa, Takahiro Nagase, Hiroshi Ueda

    Journal of Biological Chemistry   Vol. 298 ( 2 ) page: 101579 - 101579   2022.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jbc.2022.101579

    PubMed

  12. Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What's behind Neuro-RACopathies. Reviewed International journal

    Marcello Scala, Masashi Nishikawa, Koh-ichi Nagata, Pasquale Striano

    Cells   Vol. 10 ( 12 ) page: 3395 - 3395   2021.12

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.

    DOI: 10.3390/cells10123395

    PubMed

  13. The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development Reviewed

    Hidenori Ito, Rika Morishita, Mariko Noda, Tomoki Ishiguro, Masashi Nishikawa, Koh-ichi Nagata

    Journal of Biological Chemistry   Vol. 297 ( 6 ) page: 101427 - 101427   2021.12

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jbc.2021.101427

    PubMed

  14. Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis Reviewed

    Kazuki Heishima, Nobuhiko Sugito, Tomoyoshi Soga, Masashi Nishikawa, Yuko Ito, Ryo Honda, Yuki Kuranaga, Hiroki Sakai, Ryo Ito, Takayuki Nakagawa, Hiroshi Ueda, Yukihiro Akao

    Journal of Clinical Investigation   Vol. 131 ( 17 )   2021.9

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    Publishing type:Research paper (scientific journal)   Publisher:American Society for Clinical Investigation  

    DOI: 10.1172/jci139933

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  15. Expression analyses of PLEKHG2, a Rho family-specific guanine nucleotide exchange factor, during mouse brain development. Reviewed

    Masashi Nishikawa, Hidenori Ito, Mariko Noda, Nanako Hamada, Hidenori Tabata, Koh-ichi Nagata

    Medical molecular morphology   Vol. 54 ( 2 ) page: 146 - 155   2021.6

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abnormalities of PLEKHG2 gene, encoding a Rho family-specific guanine nucleotide exchange factor, are involved in microcephaly with intellectual disability. However, not only the role of PLEKHG2 in the developmental process but also its expression profile is unknown. In this study, we prepared a specific antibody against PLEKHG2 and carried out expression analyses with mouse tissues. In western blotting, PLEKHG2 exhibited a tissue-dependent expression profile in adult mouse and was expressed in a developmental stage-dependent manner in brain. Then, in immunohistochemical analyses, while PLEKHG2 was observed in the cortical plate and ventricular zone surface of the cerebral cortex at embryonic day 14, it came to be distributed throughout the cerebral cortex in layer II/III and V during corticogenesis. PLEKHG2 was also detected mainly in the nucleus of neurons in the hippocampal CA regions and dentate gyrus at P7. Notably, the nuclear accumulation disappeared at P30 and PLEKHG2 came to be located at the axons and/or dendrites at this time point. Moreover, in vitro immunofluorescence revealed that PLEKHG2 was at least partially localized at both excitatory and inhibitory synapses in primary cultured hippocampal neurons. These results suggest roles of PLEKHG2 in the development of the central nervous tissue and synaptic function.

    DOI: 10.1007/s00795-020-00275-1

    PubMed

    Other Link: https://link.springer.com/article/10.1007/s00795-020-00275-1/fulltext.html

  16. Expression Analyses of Mediator Complex Subunit 13-Like: A Responsible Gene for Neurodevelopmental Disorders during Mouse Brain Development. Reviewed International journal

    Nanako Hamada, Ikuko Iwamoto, Masashi Nishikawa, Koh-ichi Nagata

    Developmental neuroscience   Vol. 43 ( 1 ) page: 43 - 52   2021.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:S. Karger AG  

    MED13L (mediator complex subunit 13-like) is a component of the mediator complex, which functions as a regulator for gene transcription. Since gene abnormalities in MED13L are responsible for neurodevelopmental disorders, MED13L is presumed to play an essential role in brain development. In this study, we prepared a specific antibody against MED13L, anti-MED13L, and analyzed its expression profile in mouse tissues with focusing on the central nervous system. In Western blotting, MED13L exhibited a tissue-dependent expression profile in the adult mouse and was expressed in a developmental stage-dependent manner in brain. In immunofluorescence analyses, MED13L was at least partially colocalized with pre- and post-synaptic markers, synaptophysin, and PSD95, in primary cultured hippocampal neurons. Immunohistochemical analyses revealed that MED13L was relatively highly expressed in ventricular zone surface of cerebral cortex, and was also located both in the cytoplasm and nucleus of neurons in the cortical plate at embryonic day 14. Then, MED13L showed diffuse cytoplasmic distribution throughout the cerebral cortex at the postnatal day (P) 30. In addition, MED13L appeared to be localized in cell type- and developmental stage-specific manners in the hippocampus and cerebellum. These results suggest that MED13L is involved in the development of the central nervous system and synaptic function.

    DOI: 10.1159/000515188

    PubMed

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Presentations 19

  1. Rac-グアニンヌクレオチド交換因子 Prex1 の神経発達における生理機能

    鳥居 紗帆, 西川 将司, 内山 由理, 後藤 直樹, 伊東 秀記, 上田 浩, 松本 直通, 永田 浩一, 木下 専

    第64回日本神経病理学会総会学術研究会/ 第66回日本神経化学会大会 合同大会  2023.7.7 

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    Event date: 2023.7

    Presentation type:Oral presentation (general)  

  2. Expression distribution of the Rac regulatory molecule Rich2 changes with neurodevelopment

    The 46th Annual Meeting of the Molecular Biology Society of Japan (MBSJ2023)  2022.11.30 

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    Event date: 2022.11 - 2022.12

  3. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

    The 95th Annual Meeting of the Japanese Biochemical Society  2022.11.10 

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    Event date: 2022.11

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

    The 54th Annual Meeting of the Japanese Society for Clinical Molecular Morphology  2022.11.4 

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    Event date: 2022.11

  5. PLEKHG2遺伝子変異による神経発達障害の発症機構の形態的解析

    永田浩一, 西川将司, 伊東秀記, 田畑秀典

    第54回日本臨床分子形態学会総会・学術集会  2022.11.4 

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    Event date: 2022.11

  6. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

    NEURO2022  2022.6.30 

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    Event date: 2022.6 - 2022.7

    Presentation type:Poster presentation  

  7. Impaired function of PLEKHG2, a Rho-guanine nucleotide-exchange factor, disrupts corticogenesis in neurodevelopmental phenotypes

    NEURO2022  2022.6.30 

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    Event date: 2022.6 - 2022.7

    Presentation type:Poster presentation  

  8. CEP152-deficiency promotes impaired centrosome duplication- and cell death-dependent dwarfism in mice

    NEURO2022  2022.7.1 

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    Event date: 2022.6 - 2022.7

  9. 知的障害責任分子RAC3の大脳発達における生理機能と分子病態機構の解明

    永田浩一, 西川将司

    第53回 日本臨床分子形態学会総会・学術集会(web)  2021.10 

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    Event date: 2021.10

  10. 発達障害責任遺伝子Rac3の神経組織における発現解析

    西川将司, 伊東秀記, 野田万理子, 浜田奈々子, 田畑秀典, 永田浩一

    第53回 日本臨床分子形態学会総会・学術集会(web)  2021.10 

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    Event date: 2021.10

  11. Pathophysiological significance of RAC3 variants in neurodevelopmental disorders

    Masashi Nishikawa, Hidenori Ito, Hidenori Tabata, Koh‐ichi Nagata

    2021.10.1 

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    Event date: 2021.9 - 2021.10

    Presentation type:Oral presentation (general)  

  12. 低分子量G蛋白質RAC3の病的バリアントによる発達障害の病態形成機構

    永田浩一, 西川将司, 伊東秀記, 田畑秀典

    第65回日本小児神経学会学術集会  2023.5.27 

  13. 知的障害責任分子 RAC3 の大脳発達における生理機能と分子病態機構の解明 Invited

    西川将司

    名古屋大学脳とこころの研究センター 第6回 拡大ワークショップ  2021.9.29 

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    Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  14. 知的障害責任分子RAC3による神経発達障害の病態メカニズム

    西川将司, 伊東秀記, 田畑 秀典, 永田浩一

    第86回日本生化学会中部支部例会・シンポジウム  2022.5.21 

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    Presentation type:Oral presentation (general)  

  15. 知的障害責任分子RAC3の大脳発達における生理機能と分子病態機構の解明

    西川将司, 伊東秀記, 田畑 秀典, 永田浩一

    第43回神経組織培養研究会  2021.11 

  16. 知的障害責任分子群RACファミリーの大脳発達における生理機能と分子病態機構の解明

    西川将司

    第20回 東海小児遺伝カンファレンス  2022.2.19 

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    Presentation type:Oral presentation (general)  

  17. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

    Masashi Nishikawa

    2023.2.18 

  18. PLEKHG2ミスセンス変異による神経発達障害の発症メカニズム

    西川将司, 伊東秀記, 田畑秀典, 永田浩一

    第65回日本小児神経学会学術集会  2023.5.25 

  19. PLEKHG2遺伝子変異による小頭症・知的障害の発症メカニズムの解析

    西川将司, 伊東秀記, 田畑秀典, 永田浩一

    第44回 神経組織培養研究会  2022.9.17 

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KAKENHI (Grants-in-Aid for Scientific Research) 6

  1. Cdc42異常に基づく小頭症・脳皮質形成異常症を伴う知的障害の病態メカニズム解析

    Grant number:23K14946  2023.4 - 2025.3

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    西川 将司

  2. 知的障害責任分子RhoGの神経発達障害メカニズムの解明

    2023 - 2025

    (公財) 川野小児医学奨学財団 

  3. J-RDMMモデル生物プロジェクト

    2022.6 - 2023.5

    西川将司

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    Authorship:Principal investigator 

  4. 大脳発達における知的障害責任分子 Rac1の生理機能と分子病態機構の解明

    2022 - 2027

    武田科学振興財団  医学系研究助成 

    西川将司

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    Authorship:Principal investigator 

  5. 知的障害責任分子Rac3の大脳発達における生理機能と分子病態機構の解明

    Grant number:21K15895  2021.4 - 2023.3

    日本学術振興会  科学研究費助成事業  若手研究

    西川 将司

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    RAC3は、細胞形態・運動制御を司るRACサブファミリーのうち、脳に高発現するサブタイプである。最近我々のグループは、RAC3 遺伝子変異が、皮質形成異常を伴う知的障害(ID)の原因となることを同定した。すなわち RAC3は脳構造形成・神経細胞発達に必須の役割を果たすことが確実視される。しかしながら、RAC3 が神経発達で果たす役割は不明で、変異によるIDの発症メカニズムも未解明である。そこで本年度は、マウスRac3 の中枢神経組織における発現プロファイルを抗 Rac3 抗体を用いて解析した。Rac3 は大脳皮質に比較的強く発現しており、発現量が発達依存的(胎生14日から生後30日)に変化することが判明した。また、成獣脳組織を生化学的に分画して得たシナプス小胞画分とシナプス後膜画分に、Rac3も濃縮されていることもわかった。海馬初代培養神経細胞における発現解析では、培養3日目で軸索に強く局在し、培養7日目では細胞質と樹状突起上にも発現していた。さらに、培養14日目では、興奮性シナプス前膜マーカーのSynaptophysin、後膜マーカーのPSD-95と部分的に共局在していた。免疫組織染色法による発現解析では、生後2、18日目の脳梁・大脳皮質・海馬領域の軸索束に強い染色が認められた。これらの結果から、Rac3 は神経細胞の軸索・樹状突起・シナプス形成に寄与することで、神経回路ネットワーク形成に関与する可能性が示された。現在、IDの原因となるRAC3変異体の性状解析・病態解析を行なっている。

  6. Pathophysiological analyses of PLEKHG2, a responsible gene for neurodevelopmental disorders, during corticogenesis

    Grant number:20K22888  2020.9 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity Start-up

    Nishikawa Masashi

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    Homozygosity of the p.Arg204Trp variation in PLEKHG2 (PLEK2) is responsible for microcephaly with intellectual disability. However, the role of PLEK2 during neurodevelopment remains unknown. In this study, we analyzed PLEK2 function during cortical development in vivo. The variant in PLEK2 (PLEK2-RW) showed decreased guanine nucleotide-exchange activity for Rac and Cdc42. Acute knockdown of PLEK2 using in utero electroporation-mediated gene transfer delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and PAK1 signaling pathways. Axon pathfinding was also impaired in PLEK2-deficient neurons. At P14, knockdown of PLEK2 was observed to cause defects in dendritic spine formation. Collectively, these results strongly suggest that PLEK2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEK2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.

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Media Coverage 1

  1. 知的障害の病態メカニズムの一端とその治療標的となる候補分子を世界で初めて特定しました

    愛知県  https://www.pref.aichi.jp/press-release/addc-laborelease-220719.html