Regulation of neurogenesis by two-hour cycle biological clock

2009 Fiscal Year Final Research Report

• Project/Area Number: 17024027
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: KAGEYAMA Ryoichiro Kyoto University, ウイルス研究所, 教授 (80224369)
• Project Period (FY): 2005 – 2009
• Keywords: 神経幹細胞 / Hes1 / Notchシグナル / オシレーション / プロニューラル遺伝子 / 短周期遺伝子発現リズム / ニューロン新生 / 成体脳

Research Abstract

In embryonic neural stem cells, Hes1 expression oscillates with a period of about two hours, and Hes1 oscillations drive oscillatory expression of the proneural gene Ngn2 and the Notch ligand Dll1. Dll1 oscillations lead to mutual activation of Notch signaling and maintenance of neural stem cells. When Hes1 expression disappears, Ngn2 is expressed in a sustained manner, thereby promoting neuronal differentiation. In the adult brain, neurogenesis from neural stem cells is essential, and neural stem cells are maintained by the Notch-Hes pathway. These results revealed the significance of the rhythmic gene Hes1 in regulation of embryonic and adult neural stem cells.

Research Products

• [Journal Article] Essential roles of Notch signaling in maintenance of neural stem cells in the developing and adult brains. (2010)
  • Author(s): Imayoshi, I., Sakamoto, M., Yamaguchi, M., Mori, K., Kaggyama, R
  • Journal Title: J. Neurosci. 30 Pages: 3489-3498
  • Peer Reviewed
• [Journal Article] Dynamic regulation of Notch signaling in neural progenitor cells. (2009)
  • Author(s): Kaggyama, R,. Ohtsuka, T., Shimojo, H., Imayoshi, I.
  • Journal Title: Curr. Opin. Cell Biol. 21 Pages: 733-740
  • Peer Reviewed
• [Journal Article] The cyclic gene Hesl contributes to diverse differentiation responses of embryonic stem cells. (2009)
  • Author(s): Kobayashi, T., Mizuno, H., Imayoshi, I., Fumsawa, C., Shirahige, K., Kageyama, R.
  • Journal Title: Genes & Dev 23 Pages: 1870-1875
  • Peer Reviewed
• [Journal Article] Dynamic Notch signaling in neural Progenitor cells and a revised view of lateral inhibition. (2008)
  • Author(s): Kageyama, R,. Ohtsuka, T., Shimojo, H., Imayoshi, I.
  • Journal Title: Nature Neurosci 11 Pages: 1247-1251
  • Peer Reviewed
• [Journal Article] Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. (2008)
  • Author(s): Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., Kageyama. R.
  • Journal Title: Nature Neurosci 11 Pages: 1153-11611
  • Peer Reviewed
• [Journal Article] Hes genes and neurogenin regulate non-neural versus neural fate specification in the dorsal telencephalic midline. (2008)
  • Author(s): Imayoshi, I., Shimogori, T., Ohtsuka, T., KageXama、R.
  • Journal Title: Development 135 Pages: 2531-2541
  • Peer Reviewed
• [Journal Article] FGF induces oscillations of Hesl expression and Ras/ERK activation. (2008)
  • Author(s): Nakayama, K., Satoh, T., Igari, A., KageXama, R.., Nishida, E.
  • Journal Title: Curr. Biol. 18 Pages: R332-R334
  • Peer Reviewed
• [Journal Article] Oscillations in Notch signaling regulate maintenance of neural progenitors. (2008)
  • Author(s): Shimojo, H., Ohtsuka, T., andKagevama, R.
  • Journal Title: Neuron 58 Pages: 52-64
  • Peer Reviewed
• [Journal Article] Ultradian oscillators in somite segmentation and other biological events. (2007)
  • Author(s): Kagevama. R. 、Yoshiura, S., Masamizu, Y, Niwa, Y.
  • Journal Title: Cold Spring Harbor Symposia on Quantiative Biology Vol.LXXII Pages: 451-457
• [Journal Article] The initiation and propagation of Hes 7 oscillation are cooperatively regulated by Fgf and Notch signaling in the somite segmentation clock. (2007)
  • Author(s): Niwa, Y, Masamizu, Y, Liu, T., Nakayama, R., Deng, C. -X., Kageyama、R.
  • Journal Title: Dev. Cell 13 Pages: 298-304
  • Peer Reviewed
• [Journal Article] Ultradian oscillations in Stat, Smad and Hesl expression in response to serum. Proc. (2007)
  • Author(s): Yoshiura, S., Ohtsuka, T., Takenaka, Y., Nagahara, H., Yoshikawa, K., Kageyama、R.
  • Journal Title: Natl. Acad. Sci. USA 104 Pages: 11292-11297
  • Peer Reviewed
• [Journal Article] The Hes gene family:repressors and oscillators that orchestrate embryogenesis. (2007)
  • Author(s): Kagevama. R., Ohtsuka, T., Kobayashi, T.
  • Journal Title: Development 134 Pages: 1243-1251
  • Peer Reviewed
• [Journal Article] A molecular insight of Hes5-dependent inhibition of myelin gene expression:old partners and new players. (2006)
  • Author(s): Liu, A., Li, J., Marin-Husstege, M., Kageyama, R., Fan, Y, Gelinas, C., Casaccia-Bonnefil, P.
  • Journal Title: EMBO J 25 Pages: 4833-4842
  • Peer Reviewed
• [Journal Article] Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis. (2006)
  • Author(s): Zhu, X., Zhang, J., Tollkuhn, J., Ohsawa, R., Bresnick, E.H., Guillemot, F., Kageyama、R., Rosenfeld, M.G.
  • Journal Title: Genes & Dev 20 Pages: 2739-2753
  • Peer Reviewed
• [Journal Article] Persistent and high levels of Hesl expression regulate boundary formation in the developing central nervous system. (2006)
  • Author(s): Baek, J.H., Hatakeyama, J., Sakamoto, S., Ohtsuka, T., Kageyama、R.
  • Journal Title: Development 133 Pages: 2467-2476
  • Peer Reviewed
• [Journal Article] Temporal regulation of Cre recombinase activity in neural stem cells. (2006)
  • Author(s): Imayoshi, I., Ohtsuka, T., Metzger, D., Chambon, P., Kageyama、R.
  • Journal Title: Genesis 44 Pages: 233-238
  • Peer Reviewed
• [Journal Article] Real-time imaging of the somite segmentation clock:revelation of unstable oscillators in the individual presomitic mesoderm cell. (2006)
  • Author(s): Masamizu, Y, Ohtsuka, T., Takashima, Y, Nagahara, H., Takenaka, Y, Yoshikawa, K., Okamura, H., Kageyama. R.
  • Journal Title: Proc. Natl. Acad. Sci. USA103 Pages: 1313-1318
  • Peer Reviewed
• [Journal Article] Visualization of embryonic neural stem cells using Hes promoters in transgenic mice. (2006)
  • Author(s): Ohtsuka, T., Imayoshi, I., Shimojo, H., Nishi, E, Kageyama. R., McConnell, S.K.
  • Journal Title: Mol. Cell. Neurosci. 31 Pages: 109-122
  • Peer Reviewed
• [Journal Article] Mashl and Math3 are required for development of branchiomotor neurons and maintenance of neural progenitors. (2005)
  • Author(s): Ohsawa, R., Ohtsuka, T., Kagevama, R.
  • Journal Title: J. Neurosci. 25 Pages: 5857-5865
  • Peer Reviewed
• [Journal Article] C/EBP phosphorylation biases multipotent cortical Precursors to generate neurons rather than astrocytes in vivo. (2005)
  • Author(s): Paquin, A., Barnabe-Heider, E, Kageyama, R., Miller, F.D.
  • Journal Title: J. Neurosci. 25 Pages: 10747-10758
  • Peer Reviewed
• [Presentation] The role of Hesl oscillations in regulation of stem/progenitor cells. (2009)
  • Author(s): Kageyama, R.
  • Organizer: The Notch Meeting.
  • Place of Presentation: Athens, Greece
  • Year and Date: 20090927-20091001
• [Presentation] Ultradian oscillators in somite segmentation and other biological events. (2009)
  • Author(s): Kageyama, R.
  • Organizer: Symposium on Developmental Biology.
  • Place of Presentation: London, UK
  • Year and Date: 20090617-20090619
• [Presentation] The role of Hesl in proliferation and differentiation of neural stem cells. (2009)
  • Author(s): Kageyama, R
  • Organizer: EMBO Workshop/ 5th Intemational Symposium on bHLH transcription factors.
  • Place of Presentation: London, UK
  • Year and Date: 20090507-20090508
• [Presentation] Ultradian oscillators in somite segmentation and other biological events. (2009)
  • Author(s): Kageyama, R.
  • Organizer: 8th International Conference on Information Processing in Cells and Tissues.
  • Place of Presentation: Ascona, Switzerland
  • Year and Date: 20090405-20090405
• [Presentation] Oscillations in Notch signaling regulate proliferation and differentiation of neural progenitor cells. (2008)
  • Author(s): Kagevama. R.
  • Organizer: 9th Intemational Congress on Cell Biology.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20081007-20081010
• [Presentation] Oscillations in Notch signaling regulate maintenance of neural progenitor cells. (2008)
  • Author(s): Kagevama. R.
  • Organizer: 18th International Congress of Eye Research.
  • Place of Presentation: Beijing, China
  • Year and Date: 20080924-20080929
• [Presentation] Oscillations in Notch signaling regulate maintenance of neural progenitors. (2008)
  • Author(s): Kagevama. R.
  • Organizer: 2nd International Congress on Stem Cells and Tissue Formation.
  • Place of Presentation: Dresden, Germany
  • Year and Date: 20080706-20080709
• [Presentation] The role of Hesl in brain development. (2007)
  • Author(s): Kagevama. R.
  • Organizer: The Notch Meeting.
  • Place of Presentation: Athens, Greece
  • Year and Date: 20070923-20070927
• [Presentation] The mechanism of ultradian oscillations in the somite segmentation and other events. (2007)
  • Author(s): Kagevama. R.
  • Organizer: 72nd Cold Spring Harbor Symposium.
  • Place of Presentation: Cold Spring Harbor, USA
  • Year and Date: 20070530-20070604
• [Presentation] Ultradian clocks that regulate somite segmentation and other events. (2007)
  • Author(s): Kageyama. R.
  • Organizer: oint Spring Meeting of the Genetics Society, the British Society for Developmental Biology and the British Society of Cell Biology.
  • Place of Presentation: Edinburgh, UK
  • Year and Date: 20070329-20070401
• [Presentation] Roles of bHLH genes in neural development. (2006)
  • Author(s): Kagevama. R.
  • Organizer: 16th Biennial Meeting of the International Society of Developmental Neuroscience.
  • Place of Presentation: Banff, Canada
  • Year and Date: 20060824-20060828
• [Presentation] Roles of Hes bHLH genes in neural development. (2006)
  • Author(s): Kageyama. R.
  • Organizer: 7th Biennial Meeting of the Asian Pacific Society for Neurochemistry.
  • Place of Presentation: Singapore
  • Year and Date: 20060702-20060705
• [Presentation] Roles of Hes genes in neural development. (2005)
  • Author(s): Kageyama. R.
  • Organizer: Cortical Development.
  • Place of Presentation: Santorini, Greece
  • Year and Date: 20050512-20050515
• [Presentation] Roles of Hes genes in neural development. (2005)
  • Author(s): Kageyama. R.
  • Organizer: 3rd International Symposium on Basic Helix-Loop-Helix Genes.
  • Place of Presentation: Rome, Italy
  • Year and Date: 20050509-20050510
• [Book] YearBook of Science & Technology(Developmental timing and oscillating gene expression.) (2010)
  • Author(s): Kageyama. R. 、Niwa, Y., Shimojo, H.
  • Total Pages: 102-104
  • Publisher: McGraw-Hill
• [Book] Systems Biology(Eds, S.Nakanishi, R. Kageyama, and D.Watanabe, Ultradian oscillation networks in somite segmentation and other biological events.) (2009)
  • Author(s): Niwa, Y, Shimojo, H., Kagevama. R.
  • Total Pages: 199-207
  • Publisher: Springer
• [Book] Transcription Factors in the Nervous System(Ed. G.Thiel, Roles of Hes bHLH factors in neural development.) (2006)
  • Author(s): Kageyama、R., Ohtsuka, T., Hatakeyama, J.
  • Total Pages: 3-22
  • Publisher: wiley-VCH Verlag
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/Kageyama/index.html
• [Patent(Industrial Property Rights)] 多能性幹細胞からの神経細胞の分化誘導方法 (2009)
  • Inventor(s): 影山龍一郎、小林妙子
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Industrial Property Number: 特許・特願2009-168045
  • Filing Date: 2009-07-16