Molecular machinery for neuronal subtype specification in the cerebellum.

• Project/Area Number: 24300138
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• 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): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2014: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2012: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 神経科学 / 発生・文化 / 脳・神経 / 発生・分化 / 脳神経疾患 / 神経化学 / 小脳 / 発生 / 幹細胞 / 神経系 / 転写因子 / 運命決定 / 変異マウス

Outline of Final Research Achievements

In this study, we generated two novel knock-in mouse lines, which are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In those mutant mice, we observed glutamatergic and GABAergic neurons ectopically produced from Atoh1-expressing VZ and Ptf1a-expressing RL, respectively, suggesting that spatial identities of cerebellar neuron progenitors are regulated by Atoh1 and Ptf1a.
Within the cerebellar VZ at early stages, we find two types of progenitors; Olig2-expressing Purkinje cell progenitors (PCPs) and Gsx1-expressing Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. The temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1.
These findings contribute to understanding spatiotemporal control of neuronal progenitor identities by transcription factors.

Research Products

• [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
• [Journal Article] In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. (2015)
  • Author(s): Ito H, Shiwaku H, Yoshida C, Homma H, Luo H, Chen X, Fujita K, Musante L, Fischer U, Frints SG, Romano C, Ikeuchi Y, Shimamura T, Imoto S, Miyano S, Muramatsu SI, Kawauchi T, Hoshino M, Sudol M, Arumughan A, Wanker EE, Rich T, Schwartz C, Matsuzaki F, Bonni A, Kalscheuer VM, Okazawa H.
  • Journal Title: Mol Psychiatry Volume: 20 Issue: 4 Pages: 459-71
  • DOI: 10.1038/mp.2014.69
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice (2015)
  • Author(s): Wright MC, Reed-Geaghan EG, Bolock AM, Fujiyama T, Hoshino M, Maricich SM
  • Journal Title: J Cell Biol Volume: 208 Issue: 3 Pages: 367-379
  • DOI: 10.1083/jcb.201407101
  • Peer Reviewed
• [Journal Article] Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons. (2014)
  • Author(s): Nishimura YV, Shikanai M, Hoshino M, Ohshima T, Nabeshima Y, Mizutani K, Nagata K, Nakajima K and Kawauchi T
  • Journal Title: Development Volume: 141 Issue: 18 Pages: 3540-3550
  • DOI: 10.1242/dev.111294
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cytoskeletal regulation of AUTS2 in neuronal migration and neuritogenesis. (2014)
  • Author(s): Hori K., Nagai T., Shan W., Sakamoto A., Taya S., Hashimoto R., Hayashi T., Abe M., Yamazaki M., Nakao K., Nishioka T., Sakimura K., Yamada K., Kaibuchi K., Hoshino M.
  • Journal Title: Cell Reports Volume: 9 Issue: 6 Pages: 2166-2179
  • DOI: 10.1016/j.celrep.2014.11.045
  • Peer Reviewed / Open Access
• [Journal Article] Genetic dissection of plexin signaling in vivo (2014)
  • Author(s): Worzfeld T, Swiercz JM, Senturk A, Genz B, Korostylev A, Deng S, Xia J, Hoshino M, Epstein JA, Chan AM, Vollmar B, Acker-Palmer A, Kuner R, Offermanns S
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 6 Pages: 2194-2199
  • DOI: 10.1073/pnas.1308418111
  • Peer Reviewed
• [Journal Article] Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. (2014)
  • Author(s): Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S, Fujiyama T, Yamada M, Chapman H, Campbell K, Magnuson MA, Wright CV, Kawaguchi Y, Ikenaka K, Takebayashi H, Ishiwata S, Ono Y, Hoshino M.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 3337-3337
  • DOI: 10.1038/ncomms4337
  • Peer Reviewed
• [Journal Article] Characterization of Olig2 expression during cerebellar development. (2014)
  • Author(s): Seto Y, Ishiwata S, Hoshino M.
  • Journal Title: Gene Expression Patterns Volume: 15(1) Issue: 1 Pages: 1-7
  • DOI: 10.1016/j.gep.2014.02.001
  • Peer Reviewed
• [Journal Article] Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons (2014)
  • Author(s): Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T, Kawaguchi Y, Nabeshima Y, Hoshino M
  • Journal Title: J Neurosci Volume: 34 Issue: 14 Pages: 4786-4800
  • DOI: 10.1523/jneurosci.2722-13.2014
  • Peer Reviewed
• [Journal Article] Infant calming responses during maternal carrying in humans and mice (2013)
  • Author(s): Gianluca Esposito, Sachine Yoshida (equal contribution)
  • Journal Title: Current Biology Volume: 23 Issue: 9 Pages: 1-7
  • DOI: 10.1016/j.cub.2013.03.041
  • Peer Reviewed
• [Journal Article] Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear (2013)
  • Author(s): Chonko KT, Jahan I, Stone J, Wright MC, Fujiyama T, Hoshino M, Fritzsch B, Maricich SM
  • Journal Title: Dev Biol Volume: 381 Issue: 2 Pages: 401-410
  • DOI: 10.1016/j.ydbio.2013.06.022
  • Peer Reviewed
• [Journal Article] A Sharp Cadherin-6 gene expression boundary in the developing mouse cortical plate demarcates future functional areal border (2013)
  • Author(s): 寺川洋平, 他4名
  • Journal Title: Cerebral Cortex Volume: (in prese) Issue: 10 Pages: 2293-2308
  • DOI: 10.1093/cercor/bhs221
  • Peer Reviewed
• [Journal Article] A sharp Cadherin-6 gene expression boundary in the developing mouse cortical plate demarcates the future functional areal border. (2013)
  • Author(s): Terakawa, et al.
  • Journal Title: Cereb Cortex Volume: (in press)
  • Peer Reviewed
• [Journal Article] GABAergic neuron specification in the spinal cord, the cerebellum, and the cochlear nucleus. (2012)
  • Author(s): Kei Hori
  • Journal Title: Neural Plast. Volume: 2012 (2012) Pages: 921732-921732
  • DOI: 10.1155/2012/921732
  • Peer Reviewed
• [Journal Article] Neuronal subtype specification in the cerebellum and dorsal hindbrain (2012)
  • Author(s): Hoshino M
  • Journal Title: Dev Growth Differ Volume: (in press) Issue: 3 Pages: 317-326
  • DOI: 10.1111/j.1440-169x.2012.01330.x
  • NAID: 10031136904
  • Peer Reviewed
• [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
• [Presentation] イハラてんかんラットの解析 (2014)
  • Author(s): 星野幹雄
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Spatiotemporal regulation of cerebellar neural progenitor identities by transcription factors (2014)
  • Author(s): Hoshino M, Seto Y, Nakatani T, Kawaguchi Y, Ikenaka K, Takebayashi H, Ono Y, Yamada M
  • Organizer: 44th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Walter E. Washington Convention Center, Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Role of Meis1 in the cerebellar development (2014)
  • Author(s): 大輪智雄，田谷真一郎，西岡朋生，中村卓郎，五飯塚僚，貝淵弘三，星野幹雄
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Analysis of the function of a psychiatric disorder-related gene during development (2014)
  • Author(s): Hoshino M, Hori K
  • Organizer: 12th Biennial Meeting of the Asian-Pacific-Society-for-Neurochemistry
  • Place of Presentation: Howard Plaza Hotel Kaohsiung Taiwan, Kaohsiung, Taiwan
  • Year and Date: 2014-08-23 – 2014-08-26
  • Invited
• [Presentation] Spatiotemporal regulation of neural progenitor identities by transcription factors (2014)
  • Author(s): Hoshino M, Seto Y, Nakatani T, Kawaguchi Y, Ikenaka K, Takebayashi H, Ono Y, Yamada M
  • Organizer: Joint Meeting of the 20th Biennial Meeting of the International Society for Developmental Neuroscience and the 5th Annual NeuroDevNet Brain Development Conference
  • Place of Presentation: Hilton Motreal Bonaventure, Montreal, Canada
  • Year and Date: 2014-07-19 – 2014-07-24
• [Presentation] Cytoskeletal regulation by AUTS2 in Neuronal migration and neuritogenesis (2014)
  • Author(s): Hori K, Nagai T, Shan W, Sakamoto A, Taya S, Abe M, Yamazaki M, Nakao K, Nishioka T, Sakimura K, Yamada K, Kaibuchi K, Hoshino M
  • Organizer: International Symposium “New Frontier of Neuropathology 2014”
  • Place of Presentation: Suzuki Memorial Hall, Tokyo Medical and Dental University, Tokyo, Japan
• [Presentation] A genetic analysis of hypothalamic development and function by using Ptf1a-genetically modified mice (2013)
  • Author(s): Fujiyama T, Nagaoka M, Kumanogoh H, Hayase Y, Funato H, Yanagisawa M, Tanaka T, Imura A, Yanagawa Y, Magnuson MA, Wright CV, Obata K, Kawaguchi Y, Nabeshima Y, Hoshino M
  • Organizer: Neuroscience 2013, Society for Neuroscience's 43rd annual meeting
  • Place of Presentation: San Diego Convention Center, San Diego, USA
• [Presentation] 小脳顆粒細胞前駆体の分化制御におけるProx1の役割 (2013)
  • Author(s): 宮下聡，瀬戸祐介，川口義弥，宗田孝之，星野幹雄
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 国立京都国際会館
• [Presentation] てんかん自然発症ラット突然変異体の解析 (2013)
  • Author(s): 田谷真一郎，早瀬ヨネ子，山田真弓，籾山俊彦，西條琢真，三浦義記，大野行弘，今奥琢士，伊原信夫，天野殖，星野幹雄
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Sox9 controls oligodendrocyte differentiation in the cerebellum (2013)
  • Author(s): 橋本了哉，増山典久，川口義弥，秋山治彦，小泉修一，星野幹雄
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Transcriptional regulation of the diversity of cerebellar GABA ergic neurons. (2012)
  • Author(s): Seto, et al.
  • Organizer: Society for Neuroscience
  • Place of Presentation: 米国ニューオーリンズカンファレンスセンタ
• [Presentation] Analysis of a rat model for human temporal lobe epilepsy (2012)
  • Author(s): Hoshino M
  • Organizer: International Synapse Research Workshop
  • Place of Presentation: 愛知県岡崎市 自然科学研究(招待講演)
• [Presentation] Neuron subtype specification in the cerebellum. (2012)
  • Author(s): Hoshino M
  • Organizer: Joint symposium between Max Planck Institute and National Center of Neurology and Psychiatry
  • Place of Presentation: ドイツ、マックスプランク研究所 リングパーク城
• [Book] Specification of cerebellar and precerebellar neurons; in "Handbook of the Cerebellum and Cerebellar Disorders" (2012)
  • Author(s): Hoshino, et al.
  • Total Pages: 13
  • Publisher: Springer
• [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
  • URL: http://www.ncnp.go.jp/nin/guide/r_diag/index.html
• [Remarks]
  • URL: http://www.ncnp.go.jp/nin/guide/r_diag/index.html