メゾ回路形成の分子機構と、その破綻による精神疾患病理の解明

• Project Area: Mesoscopic neurocircuitry: towards understanding of the functional and structural basis of brain information processing
• Project/Area Number: 25115733
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: 星野 幹雄 独立行政法人国立精神・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): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 神経科学 / 精神疾患 / てんかん / 発生 / 神経細胞 / 脳神経 / メゾ神経回路 / 精神発達遅滞

Outline of Annual Research Achievements

近年、精神発達障害やてんかんなどの精神疾患が、脳回路の機能異常として理解されるようになってきた。遺伝要因の関与と、小児期の発症の多さ、そしててんかんが焦点を持つことが多いことなどから、これら疾患の発症原因の一つはメゾ神経回路の形成障害と考えられる。しかし、メゾ神経回路の形成機構およびその異常によってもたらされる病態については、未だに未解明の部分が多い。そこで本研究では、１イハラてんかんラット(IER)の解析、２各種精神疾患に関連するAUTS2遺伝子の機能解明を目指した。
1我々は、これまでにイハラてんかんラット(IER)の原因遺伝子を同定し、その遺伝子産物が、神経突起伸長促進作用、および分子間相互反発を介した神経突起束化抑制作用と細胞間隔保持作用によって、神経回路網形成（特に抑制神経回路系）に関与し、てんかん発症の抑制に役立っていることを明らかにした。また、国立精神神経医療研究センターの「精神遅滞・てんかんリサーチリソース」からこの原因遺伝子の異常によって引き起こされるてんかん症例のスクリーニングに着手した。さらにIERの表現型解析、ヒト疾患のスクリーニング、およりこの原因遺伝子のファミリー遺伝子の解析、なども精力的に進めている。
2 統合失調症、自閉症スペクトラム障害、ADHD、薬物依存など、様々な精神疾患に後半に関連する遺伝子AUTS2の機能はこれまで不明であった。我々は、この遺伝子産物が低分子量G蛋白質の活性制御を介して神経細胞内のアクチン細胞骨格系を再構成すること、それによって神経細胞移動や神経突起伸長に関与していることを明らかにした(Cell Reports 2014)。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [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
• [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
• [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