Elucidation of molecular mechanisms of acquisition of individuality and differentiation of various types of neurons in the cerebellum

• Project/Area Number: 18H02538
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• 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)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 神経発生 / 小脳 / 転写因子 / 細胞分化 / サイクリンD1 / PROX1 / ATOH1 / MEIS1 / 発生 / 神経系 / 神経細胞 / 顆粒細胞 / 神経前駆細胞 / 小脳発生 / 神経回路 / 脳神経 / CCND1 / 神経科学 / 発生・分化 / 解剖学 / 脳・神経 / 神経

Outline of Final Research Achievements

It was found that granule cell progenitors (GCPs) in the cerebellum progressively lose their "undifferentiated" and "proliferative" nature and eventually differentiate into granule cells. Furthermore, in this stepwise transition, cyclin D1, which was known to activate cell proliferation, was found to stabilize the ATOH1 protein via phosphorylation, thereby maintaining the undifferentiated nature of GCPs. It was also revealed that the WNT protein, which increases with brain development, and the PROX1 molecule whose expression is induced by the WNT protein, gradually decrease the amount of cyclin D1, thereby accelerating GC development.

Academic Significance and Societal Importance of the Research Achievements

本研究では、顆粒細胞(GCs)という神経細胞の新しい発生メカニズムとその分子基盤に関して新しい知見を多く見出すことができた。これらの成果は、顆粒細胞の発生機構だけではなく、進化的な小脳皮質の拡大機構や顆粒細胞のガン化のメカニズムに関しても多くの示唆に富んでいる。また、今回注目している分子や発生メカニズムは小脳にとどまらない。大脳皮質をはじめとする各脳領域で、これらの分子や発生メカニズムは共通しているため、小脳の研究が、脳全体の共通原理の創出につながっていくことが、今後大いに期待される。

Research Products

• [Journal Article] Transit Amplifying Progenitors in the Cerebellum: Similarities to and Differences from Transit Amplifying Cells in Other Brain Regions and between Species (2022)
  • Author(s): Miyashita Satoshi、Hoshino Mikio
  • Journal Title: Cells Volume: 11 Issue: 4 Pages: 726-726
  • DOI: 10.3390/cells11040726
  • Peer Reviewed / Open Access
• [Journal Article] Potential involvement of DSCAML1 mutations in neurodevelopmental disorders (2021)
  • Author(s): Ogata S, Hashizume K, Hayase Y, Kanno Y, Hori K, Balan S, Yoshikawa T, Takahashi H, Taya S, Hoshino M
  • Journal Title: Genes Cells Volume: (3) Issue: 3 Pages: 136-151
  • DOI: 10.1111/gtc.12831
  • Peer Reviewed / Open Access
• [Journal Article] Notch Signaling between Cerebellar Granule Cell Progenitors (2021)
  • Author(s): Adachi Toma、Miyashita Satoshi、Yamashita Mariko、Shimoda Mana、Okonechnikov Konstantin、Chavez Lukas、Kool Marcel、Pfister Stefan M.、Inoue Takafumi、Kawauchi Daisuke、Hoshino Mikio
  • Journal Title: eneuro Volume: 8 Issue: 3 Pages: 0468-20
  • DOI: 10.1523/eneuro.0468-20.2021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication (2020)
  • Author(s): Yamashiro Kunihiko、Hori Kei、Lai Esther S.K.、Aoki Ryo、Shimaoka Kazumi、Arimura Nariko、Egusa Saki F.、Sakamoto Asami、Abe Manabu、Sakimura Kenji、Watanabe Takaki、Uesaka Naofumi、Kano Masanobu、Hoshino Mikio
  • Journal Title: iScience Volume: 23 Issue: 12 Pages: 101820-101820
  • DOI: 10.1016/j.isci.2020.101820
  • NAID: 120006979860
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility. (2020)
  • Author(s): Hayase Y, Amano S, Hashizume K, Tominaga T, Miyamoto H, Kanno Y, Ueno-Inoue Y, Inoue T, Yamada M, Ogata S, Balan S, Hayashi K, Miura Y, Tokudome K, Ohno Y, Nishijo T, Momiyama T, Yanagawa Y, Takizawa A, Mashimo T, Serikawa T, Sekine A, Nakagawa E, Takeshita E, Yoshikawa T, Waga C, Inoue K, Goto YI, Nabeshima Y, et al.
  • Journal Title: Acta Neuropathol Commun. Volume: 8 Issue: 1 Pages: 206-206
  • DOI: 10.1186/s40478-020-01082-6
  • Peer Reviewed / Open Access
• [Journal Article] DSCAM regulates delamination of neurons in the developing midbrain (2020)
  • Author(s): Arimura Nariko、Okada Mako、Taya Shinichiro、Dewa Ken-ichi、Tsuzuki Akiko、Uetake Hirotomo、Miyashita Satoshi、Hashizume Koichi、Shimaoka Kazumi、Egusa Saki、Nishioka Tomoki、Yanagawa Yuchio、Yamakawa Kazuhiro、Inoue Yukiko U.、Inoue Takayoshi、Kaibuchi Kozo、Hoshino Mikio
  • Journal Title: Science Advances Volume: 6 Issue: 36 Pages: 1693-1693
  • DOI: 10.1126/sciadv.aba1693
  • Peer Reviewed / Open Access
• [Journal Article] AUTS2 regulation of synapses for proper synaptic inputs and social communication. (2020)
  • Author(s): Hori Kei、Yamashiro Kunihiko、Nagai Taku、... Yamada Mitsuhiko、Yamada Kiyofumi、Hoshino Mikio
  • Journal Title: iScience Volume: ー Issue: 6 Pages: 101183-101183
  • DOI: 10.1016/j.isci.2020.101183
  • Peer Reviewed / Open Access
• [Journal Article] YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis (2019)
  • Author(s): Pajtler KW、Wei Y、Okonechnikov K、et al.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3914-3914
  • DOI: 10.1038/s41467-019-11884-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of transcription factors and signaling molecules in the cerebellar granule cell development (2019)
  • Author(s): Shiraishi Ryo D.、Miyashita Sathoshi、Yamashita Mariko、Adachi Toma、Shimoda Mana M.、Owa Tomoo、Hoshino Mikio
  • Journal Title: Gene Expression Patterns Volume: 34 Pages: 119068-119068
  • DOI: 10.1016/j.gep.2019.119068
  • Peer Reviewed / Open Access
• [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
• [Presentation] Novel function of Down Syndrome Cell Adhesion Molecule in mammalian brain development. (2021)
  • Author(s): Hosino M
  • Organizer: Fujiyhara Seminar, ONLINE, 2021(Aug 30-31)
  • Int'l Joint Research / Invited
• [Presentation] AUTS2の神経発生における機能と病理 (2020)
  • Author(s): 星野幹雄、堀啓
  • Organizer: NPBPPP合同年会
  • Invited
• [Presentation] Neuronal progenitors and synapses in psychiatric disease mouse model (2020)
  • Author(s): Hoshino M, Hori K
  • Organizer: 日本神経科学会大会
  • Invited
• [Presentation] 小脳顆粒細胞分化の分子機構と発達期曝露による影響評価 (2020)
  • Author(s): 星野幹雄, 宮下聡
  • Organizer: 日本毒性学会年会
  • Invited
• [Presentation] 脳の性分化のための新たな分子機構 (2019)
  • Author(s): 星野幹雄
  • Organizer: 第46回日本毒性学会学術年会
  • Invited
• [Presentation] Notch signaling in the cerebellar granule cell development. (2019)
  • Author(s): Adachi T, Miyashita S, Yamashita M, Shiraishi R, Shimoda M, Owa T, Hoshino M
  • Organizer: Society for Neuroscience 2019
  • Int'l Joint Research
• [Presentation] Auts2 is required for neurogenesis in cerebral cortex. (2019)
  • Author(s): 嶋岡可純， 堀啓， 坂本亜沙美， 阿部学， 崎村建司， 星野幹雄
  • Organizer: NEURO2019
• [Presentation] 自閉症感受性遺伝子Auts2変異により引き起こるシナプス形成障害およびマウス行動異常の病態解析 (2019)
  • Author(s): 堀啓， 山城邦比古， 永井拓， Shan Wei， 江草早紀， 嶋岡可純， 郷康宏， 辰本将司， 菅野康太， 坂本亜沙美， 阿部学， 崎村健司， 惣谷和宏， 功刀浩， 山田清文， 星野幹雄
  • Organizer: 第42回日本分子生物学会年会
• [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
  • 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
• [Remarks] 病態生化学研究部ホームページ
  • URL: https://byosei-neuroscience-institute.ncnp.go.jp
• [Remarks] 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 ホームページ
  • URL: https://www.ncnp.go.jp/nin/guide/r_diag/index.html