Neuronal specification and differentiation in the cerebellum

• Project/Area Number: 15H04268
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Hoshino Mikio 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 病態生化学研究部, 部長 (70301273)
• Research Collaborator: OWA tomoo ; MIYASHITA satoshi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 小脳 / 転写因子 / 発生 / 神経科学 / 発生・分化 / 解剖学 / 脳・神経 / 遺伝学

Outline of Final Research Achievements

Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. We found that Meis1 is expressed in granule cell lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules. Knockdown/knockout experiments for Meis1 as well as in vitro assays show that Meis1 binds to an upstream sequence of Pax6 to enhance its transcription in GCPs/GCs. Furthermore, we found that the Meis1-Pax6 pathway increases the expression of Smad proteins to upregulate BMP signaling, leading to degradation of Atoh1 in the inner EGL, which contributes to differentiation from GCPs to GCs. Thus, this work reveals multiple functions of Meis1 in GC development and gives insights into the general understanding of the molecular machinery underlying neural differentiation from neural progenitors.

Academic Significance and Societal Importance of the Research Achievements

今回の知見により、これまで個別に明らかにされてきた小脳顆粒細胞の発生の分子機構を、MEIS1というハブによって統合的に理解することが可能となった。これは小脳にとどまらず、様々な脳部位での神経前駆細胞から神経細胞が生み出されるしくみの理解につながると考えられる。また、MEIS1は一部の髄芽腫において異常に強く発現しており、髄芽腫の発症に関与している可能性も考えられるために、今回の研究成果は広く今後の小脳癌研究の発展に寄与すると考えられる。

Research Products

• [Journal Article] Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride (2019)
  • Author(s): Takizawa Hotake、Hara Yuko、Mizobe Yoshitaka、Ohno Taisuke、Suzuki Sadafumi、Inoue Ken、Takeshita Eri、Shimizu-Motohashi Yuko、Ishiyama Akihiko、Hoshino Mikio、Komaki Hirofumi、Takeda Shin’ichi、Aoki Yoshitsugu
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3807-3807
  • DOI: 10.1038/s41598-019-40421-z
  • Peer Reviewed / Open Access
• [Journal Article] Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain (2018)
  • Author(s): Fujiyama Tomoyuki、Miyashita Satoshi、Tsuneoka Yousuke、Kanemaru Kazumasa、Kakizaki Miyo、Kanno Satomi、Ishikawa Yukiko、Yamashita Mariko、Owa Tomoo、Nagaoka Mai、Kawaguchi Yoshiya、Yanagawa Yuchio、Magnuson Mark A.、Muratani Masafumi、Shibuya Akira、Nabeshima Yo-ichi、Yanagisawa Masashi、Funato Hiromasa、Hoshino Mikio
  • Journal Title: Cell Reports Volume: 24 Issue: 1 Pages: 79-94
  • DOI: 10.1016/j.celrep.2018.06.010
  • NAID: 120006491717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of Pax6-IRES-EGFP knock-in mouse via the cloning-free CRISPR/Cas9 system to reliably visualize neurodevelopmental dynamics (2018)
  • Author(s): Inoue Yukiko U.、Morimoto Yuki、Hoshino Mikio、Inoue Takayoshi
  • Journal Title: Neuroscience Research Volume: in press Pages: 1-7
  • DOI: 10.1016/j.neures.2018.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of AMPAR?Palmitoylation Aggravates Seizure Susceptibility (2018)
  • Author(s): Itoh Masayuki、Yamashita Mariko、Kaneko Masaki、Okuno Hiroyuki、Abe Manabu、Yamazaki Maya、Natsume Rie、Yamada Daisuke、Kaizuka Toshie、Suwa Reiko、Sakimura Kenji、Sekiguchi Masayuki、Wada Keiji、Hoshino Mikio、Mishina Masayoshi、Hayashi Takashi
  • Journal Title: The Journal of Neuroscience Volume: 38 Issue: 47 Pages: 10220-10235
  • DOI: 10.1523/jneurosci.1590-18.2018
  • Peer Reviewed / Open Access
• [Journal Article] Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway (2018)
  • Author(s): Sakikubo Morito、Furuyama Kenichiro、Horiguchi Masashi、Hosokawa Shinichi、Aoyama Yoshiki、Tsuboi Kunihiko、Goto Toshihiko、Hirata Koji、Masui Toshihiko、Dor Yuval、Fujiyama Tomoyuki、Hoshino Mikio、Uemoto Shinji、Kawaguchi Yoshiya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15812-15812
  • DOI: 10.1038/s41598-018-34093-4
  • NAID: 120006715479
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3?Ubiquitin Ligases and Intronic miR-140 (2018)
  • Author(s): Ambrozkiewicz MC、Schwark M、Kishimoto-Suga M、Borisova E、Hori K、Salazar-L?zaro A、Rusanova A、Altas B、Piepkorn L、Bessa P、Schaub T、Zhang X、Rabe T、Ripamonti S、Ros?rio M、Akiyama H、Jahn O、Kobayashi T、Hoshino M、Tarabykin V、Kawabe H
  • Journal Title: Neuron Volume: 100 Issue: 5 Pages: 1097-1115
  • DOI: 10.1016/j.neuron.2018.10.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C‐terminal palmitoylation‐deficient mice (2018)
  • Author(s): Itoh Masayuki、Okuno Hiroyuki、Yamada Daisuke、Yamashita Mariko、Abe Manabu、Natsume Rie、Kaizuka Toshie、Sakimura Kenji、Hoshino Mikio、Mishina Masayoshi、Wada Keiji、Sekiguchi Masayuki、Hayashi Takashi
  • Journal Title: Neuropsychopharmacology Reports Volume: 39 Issue: 1 Pages: 61-66
  • DOI: 10.1002/npr2.12044
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive and cell-type-based characterization of the dorsal midbrain during development (2018)
  • Author(s): Arimura Nariko、Dewa Ken-ichi、Okada Mako、Yanagawa Yuchio、Taya Shin-ichiro、Hoshino Mikio
  • Journal Title: Genes to Cells Volume: 24 Issue: 1 Pages: 41-59
  • DOI: 10.1111/gtc.12656
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay (2017)
  • Author(s): Hanai S, Sukigara S, Dai H, Owa T, Horike SI, Otsuki T, Saito T, Nakagawa E, Ikegaya N, Kaido T, Sato N, Takahashi A, Sugai K, Saito Y, Sasaki M, Hoshino M, Goto YI, Koizumi S, Itoh M
  • Journal Title: The American Journal of Pathology Volume: 187 Issue: 5 Pages: 1177-1185
  • DOI: 10.1016/j.ajpath.2017.01.015
  • Peer Reviewed
• [Journal Article] Specification of Cerebellar Neurons (2016)
  • Author(s): Hoshino M
  • Journal Title: Essentials of Cerebellum and Cerebellar Disorders Volume: 1 Pages: 143-147
  • Peer Reviewed
• [Journal Article] Precerebellar Nuclei (2016)
  • Author(s): Yamada M, Hoshino M
  • Journal Title: Essentials of Cerebellum and Cerebellar Disorders Volume: 1 Pages: 63-67
  • Peer Reviewed
• [Journal Article] AUTS2(Autism Susceptibility Candidate 2) (2016)
  • Author(s): 星野幹雄
  • Journal Title: 分子精神医学 Volume: 16 Pages: 53-55
• [Journal Article] Origins of oligodendrocytes in the cerebellum, whose development is controlled by the transcription factor, Sox9 (2016)
  • Author(s): Hashimoto R, Hori K, Owa T, Miyashita S, Dewa K, Masuyama N, Sakai K, Hayase Y, Seto Y, Inoue YU, Inoue T, Ichinohe N, Kawaguchi Y, Akiyama H, Koizumi S, Hoshino M
  • Journal Title: Mech Dev Volume: 140 Pages: 25-40
  • DOI: 10.1016/j.mod.2016.02.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory. (2015)
  • Author(s): Hori K, Nagai T, Shan W, Sakamoto A, Abe M, Yamazaki M, Sakimura K, Yamada K, Hoshino M.
  • Journal Title: PLoS One Volume: 30 Issue: 12 Pages: e0145979-e0145979
  • DOI: 10.1371/journal.pone.0145979
  • Peer Reviewed / Open Access
• [Journal Article] Classic cadherin expressions balance postnatal neuronal positioning and dendrite dynamics to elaborate the specific cytoarchitecture of the mouse cortical area (2015)
  • Author(s): Egusa SF, Inoue YU, Asami J, Terakawa YW, Hoshino M, Inoue T
  • Journal Title: Neurosci Res Volume: 105 Pages: 49-64
  • DOI: 10.1016/j.neures.2015.09.006
  • Peer Reviewed
• [Presentation] AUTS2 gene and psychiatric disorders (2018)
  • Author(s): Hoshino M, Hori K
  • Organizer: 第41回日本神経科学大会
  • Invited
• [Presentation] Loss of Auts2 induces the defects of synaptic function and cognitive brain functions (2018)
  • Author(s): Hori K, Nagai T, Shan W, Yamad M, Shiraishi R, Sakamoto A, Kanno K, Abe M, Yamada K, Sakimura K, Hoshino M
  • Organizer: 新学術領域個性創発脳第1回国際シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] AUTS2 is required for neurogenesis in cerebral cortex (2018)
  • Author(s): 嶋岡可純，堀啓，坂本亜沙美，阿部学，崎村健司，星野幹雄
  • Organizer: 第12回神経発生討論会
• [Presentation] Role of Meis1 in the cerebellar development. (2018)
  • Author(s): 大輪智雄, 田谷真一郎, 宮下聡, 西岡朋生, 中村卓郎, 後飯塚僚, 貝淵弘三, 星野幹雄
  • Organizer: 第40回日本生物学的精神医学会 第61回日本神経化学大会合同年会
• [Presentation] The role of AUTS2 gene in the corticogenesis (2018)
  • Author(s): 嶋岡可純，堀啓，坂本亜沙美，阿部学，崎村健司，星野幹雄嶋岡可純，堀啓，坂本亜沙美，阿部学，崎村健司，星野幹雄
  • Organizer: 第40回日本生物学的精神医学会 第61回日本神経化学大会合同年会
• [Presentation] 小脳神経細胞の発生プログラム (2017)
  • Author(s): 星野幹雄
  • Organizer: 2016年度 第7回小脳研究会 学術集会・総会
  • Place of Presentation: アルカディア市ヶ谷
  • Year and Date: 2017-01-20
  • Invited
• [Presentation] Role of Meis1 in the cerebellar development (2016)
  • Author(s): Owa T, Taya S, Miyashita S, Nishioka T, Kaibuchi K, Hoshino M
  • Organizer: Neuroscience2016
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2016-11-14
  • Int'l Joint Research
• [Presentation] 精神疾患関連遺伝子AUTS2の生理機能と病理 (2016)
  • Author(s): 星野幹雄
  • Organizer: 第39回日本神経科学大会シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-07-21
• [Presentation] 脳神経系の発生と精神疾患そして脳進化-Autism Susceptibility Candidate2 遺伝子の研究を通して- (2016)
  • Author(s): 星野幹雄
  • Organizer: タイムシグナルと制御シンポジウム
  • Place of Presentation: 筑波大学下田臨海実験センター
  • Year and Date: 2016-06-10
  • Invited
• [Presentation] Cytoplasmic function of AUTS2 in neural network formation (2015)
  • Author(s): Hoshino M, Nagai T, Shen W, Sakamoto A, Taya S, Hashimoto R, Hayashi T, Abe M, Yamazaki M, Nakao K, Nishioka T, Sakimura K, Yamada K, Kaibuchi K, Hori K
  • Organizer: Society for Neuroscience 45th annual meeting
  • Place of Presentation: McCormick Place, Chicago, IL, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Analysis of autism susceptibility candidate 2 gene during development (2015)
  • Author(s): Hoshino M, Hori K
  • Organizer: Tohoku Forum for Creativity, Frontiers of Brain Science, “Development and Disease” symposium
  • Place of Presentation: Tohoku University, Sendai, Japan
  • Year and Date: 2015-08-24
  • Int'l Joint Research / Invited
• [Presentation] 各種精神疾患とAUTS2遺伝子、そしてヒトの進化 (2015)
  • Author(s): 星野幹雄
  • Organizer: 平成27年度生理学研究所研究会「シナプスの構造構築と機能発現の分子基盤」
  • Place of Presentation: 生理学研究所, 岡崎
  • Year and Date: 2015-06-18
  • Invited
• [Presentation] Physiological and pathological analyses of an autism-related gene (2015)
  • Author(s): Hoshino M
  • Organizer: EMBO Workshop on Cortical Development in Health and Disease
  • Place of Presentation: Weizmann Institute of Science, Rehovot, Israel
  • Year and Date: 2015-04-26
  • Int'l Joint Research / Invited