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Elucidation of the neural circuitry mechanism causing brain dysfunction in MICPCH syndrome due to X chromosome inactivation.

Research Project

Project/Area Number 19H03544
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionShinshu University

Principal Investigator

Tabuchi Katsuhiko  信州大学, 学術研究院医学系, 教授 (20546767)

Co-Investigator(Kenkyū-buntansha) 森 琢磨  信州大学, 学術研究院医学系, 助教 (70545798)
付 ゆう  信州大学, 学術研究院医学系, 助教 (30830301)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
KeywordsCASK / MICPCH症候群 / X染色体不活性化 / 小脳低形成 / 小脳顆粒細胞 / neurexin / マウスモデル / 神経発達障害
Outline of Research at the Start

MICPCH症候群は、CASK遺伝子の異常によって引き起こされるX連鎖精神遅滞症候群で、患者の殆どは女性である。MICPCH症候群の患者では、X染色体不活性化によりCASK正常細胞と異常細胞がモザイク状に分布していると考えられる。本研究は、CASKのヘテロノックアウトマウスをモデルとし、X染色体不活性化がMICPCH症候群の病態形成に与える影響について研究を行う。このため、X染色体不活性化ニューロンを識別し、CASK異常ニューロンの脳内での分布の偏りと症状との相関関係、CASK発現ニューロンと非発現ニューロン間での微小回路の形成の有無、点頭てんかん及び小脳低形成の発症機序について解明を目指す。

Outline of Final Research Achievements

MICPCH syndrome is a neurodevelopmental disorder characterized by cerebellar hypoplasia. It is known to be caused by heterozygosity of the CASK gene on the X chromosome. In this study, we investigated how X chromosome inactivation is involved in cerebellar hypoplasia using mouse models. By crossing CASK knockout mice with Hprt-eGFP mice, in which the EGFP expression cassette is on the X chromosome, we differentiated between CASK positive and negative neurons in the CASK heterozygote knockout brains. We also conducted cerebellar granule cell culture experiments to investigate the molecular mechanism involved in cerebellar hypoplasia. Through these experiments, we found that CASK deficiency caused apoptosis in cerebellar granule cells in a cell-autonomous manner. Additionally, we discovered that the disruption of CASK and Liprin-a2 binding caused by mutations within the CaMK domain of CASK is involved in the molecular mechanism underlying cerebellar hypoplasia in MICPCH syndrome.

Academic Significance and Societal Importance of the Research Achievements

MICPCH症候群は、日本ではCASK異常症として小児慢性特定疾患に指定されており、重篤な神経発生異常にもかかわらず、治療法が存在しない。特に、小脳低形成は進行性で、徐々に小脳が委縮していくものであり、これを食い止める手段を発見することは急務であるが、現在の所、病態形成メカニズムが不明であるため困難な状況である。本研究で、CASKの異常による小脳顆粒細胞のアポトーシスと、Liprin-a2を介した分子メカニズムが病態形成に関与していることが発見された。このことは、これらの分子を標的とした治療法が開発できる可能性が見えてきたことを意味しており、社会的意義が大きい。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020 Other

All Journal Article (14 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 14 results,  Open Access: 14 results) Remarks (3 results)

  • [Journal Article] Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome2023

    • Author(s)
      Guo Qi、Kouyama-Suzuki Emi、Shirai Yoshinori、Cao Xueshan、Yanagawa Toru、Mori Takuma、Tabuchi Katsuhiko
    • Journal Title

      Cells

      Volume: 12 Issue: 8 Pages: 1177-1177

    • DOI

      10.3390/cells12081177

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice2022

    • Author(s)
      Pang Bo、Mori Takuma、Badawi Moataz、Zhou Mengyun、Guo Qi、Suzuki-Kouyama Emi、Yanagawa Toru、Shirai Yoshinori、Tabuchi Katsuhiko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 14 Pages: 7927-7927

    • DOI

      10.3390/ijms23147927

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins2022

    • Author(s)
      Uemura T, Suzuki-Kouyama E, Kawase S, Kurihara T, Yasumura M, Yoshida T, Fukai S, Yamazaki M, Fei P, Abe M, Watanabe M, Sakimura K, Mishina M, Tabuchi K
    • Journal Title

      Cell Reports

      Volume: 39 Issue: 1 Pages: 110624-110624

    • DOI

      10.1016/j.celrep.2022.110624

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus2022

    • Author(s)
      Kim D.、Jung H.、Shirai Y.、Kim H.、Kim J.、Lim D.、Mori T. 他20名
    • Journal Title

      Biological Psychiatry

      Volume: 91 Issue: 9 Pages: 821-831

    • DOI

      10.1016/j.biopsych.2021.12.016

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MicroRNA 142-5p promotes tumor growth in oral squamous cell carcinoma via the PI3K/AKT pathway by regulating PTEN2021

    • Author(s)
      Iizumi Seiichiro、Uchida Fumihiko、Nagai Hiroki、Takaoka Shohei、Fukuzawa Satoshi、Kanno Naomi Ishibashi、Yamagata Kenji、Tabuchi Katsuhiko、Yanagawa Toru、Bukawa Hiroki
    • Journal Title

      Heliyon

      Volume: 7 Issue: 10 Pages: e08086-e08086

    • DOI

      10.1016/j.heliyon.2021.e08086

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nasal molding prevents relapse of nasal deformity after primary rhinoplasty in patients with unilateral complete cleft lip: An outcomes‐based comparative study of palatal plate alone versus nasoalveolar molding2021

    • Author(s)
      Aihara Yukiko、Yanagawa Toru、Sasaki Masahiro、Sasaki Kaoru、Shibuya Yoichiro、Adachi Koji、Togashi Shinji、Takaoka Shohei、Tabuchi Katsuhiko、Bukawa Hiroki、Sekido Mitsuru
    • Journal Title

      Clinical and Experimental Dental Research

      Volume: 8 Issue: 1 Pages: 197-208

    • DOI

      10.1002/cre2.502

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex2021

    • Author(s)
      Mehta Anuradha、Shirai Yoshinori、Kouyama-Suzuki Emi、Zhou Mengyun、Yoshizawa Takahiro、Yanagawa Toru、Mori Takuma、Tabuchi Katsuhiko
    • Journal Title

      Cells

      Volume: 10 Issue: 10 Pages: 2724-2724

    • DOI

      10.3390/cells10102724

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK12021

    • Author(s)
      Badawi Moataz、Mori Takuma、Kurihara Taiga、Yoshizawa Takahiro、Nohara Katsuhiro、Kouyama-Suzuki Emi、Yanagawa Toru、Shirai Yoshinori、Tabuchi Katsuhiko
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 14 Pages: 706494-706494

    • DOI

      10.3389/fnmol.2021.706494

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior2021

    • Author(s)
      Kim Seungjoon、Park Dongseok、Kim Jinhu、Kim Dongwook、Kim Hyeonho、Mori Takuma、Jung Hyeji、Lee Dongsu、Hong Sookyung、Jeon Jongcheol、Tabuchi Katsuhiko、Cheong Eunji、Kim Jaehoon、Um Ji Won、Ko Jaewon
    • Journal Title

      Cell Reports

      Volume: 36 Issue: 3 Pages: 109417-109417

    • DOI

      10.1016/j.celrep.2021.109417

    • Related Report
      2021 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum2021

    • Author(s)
      Lai Esther Suk King、Nakayama Hisako、Miyazaki Taisuke、Nakazawa Takanobu、Tabuchi Katsuhiko、Hashimoto Kouichi、Watanabe Masahiko、Kano Masanobu
    • Journal Title

      Frontiers in Neural Circuits

      Volume: 15 Pages: 676891-676891

    • DOI

      10.3389/fncir.2021.676891

    • Related Report
      2021 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Non-microtubule tubulin-based backbone and subordinate components of postsynaptic density lattices2021

    • Author(s)
      Suzuki Tatsuo、Terada Nobuo、Higashiyama Shigeki、Kametani Kiyokazu、Shirai Yoshinori、Honda Mamoru、Kai Tsutomu、Li Weidong、Tabuchi Katsuhiko
    • Journal Title

      Life Science Alliance

      Volume: 4 Issue: 7 Pages: e202000945-e202000945

    • DOI

      10.26508/lsa.202000945

    • Related Report
      2021 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice2021

    • Author(s)
      Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 1848-1848

    • DOI

      10.1038/s41467-021-22059-6

    • NAID

      120006996978

    • Related Report
      2021 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] DNA repair protein RAD51 enhances the CRISPR/Cas9-mediated knock-in efficiency in brain neurons2020

    • Author(s)
      Kurihara Taiga、Kouyama-Suzuki Emi、Satoga Michiru、Li Xue、Badawi Moataz、Thiha、Baig Deeba Noreen、Yanagawa Toru、Uemura Takeshi、Mori Takuma、Tabuchi Katsuhiko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 524 Issue: 3 Pages: 621-628

    • DOI

      10.1016/j.bbrc.2020.01.132

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibition of DNA ligase IV enhances the CRISPR/Cas9-mediated knock-in efficiency in mouse brain neurons2020

    • Author(s)
      Cao Xueshan、Kouyama-Suzuki Emi、Pang Bo、Kurihara Taiga、Mori Takuma、Yanagawa Toru、Shirai Yoshinori、Tabuchi Katsuhiko
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 533 Issue: 3 Pages: 449-457

    • DOI

      10.1016/j.bbrc.2020.09.053

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Remarks] CASK異常症治療への新たな一歩:AIを用いて小脳低形成が起こるメカニズムを解明

    • URL

      https://www.shinshu-u.ac.jp/faculty/medicine/topics/2023/04/18174157.php

    • Related Report
      2021 Annual Research Report
  • [Remarks] 信州大学医学部分子細胞生理学教室

    • URL

      https://www.shinshu-u.ac.jp/faculty/medicine/chair/i-2seiri/ja/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 信州大学医学部分子細胞生理学教室

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-2seiri/ja/index.html

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2024-01-30  

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