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The intracellular mechanism for regulation of mammalian neural development

Research Project

Project/Area Number 09470030
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

KAGEYAMA Ryoichiro  Inst. for Virus Res., Kyoto Univ., Professor, ウイルス研究所, 教授 (80224369)

Co-Investigator(Kenkyū-buntansha) 影山 龍一郎  京都大学, ウイルス研究所, 教授 (80224369)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 1999: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1998: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1997: ¥5,500,000 (Direct Cost: ¥5,500,000)
KeywordsNotch / Hes / bHLH / neuron / glia / neural precursor cell / retrovirus / knock-out mouse / 神経分化 / 標的遺伝子破壊 / 側方抑制 / ヘリックス・ループ・ヘリックス / Mash1
Research Abstract

In mammalian neural development, initially neural precursor cells are maintained but later they differentiate into neurons and glial cells that form a complex nervous system. To elucidate the intracellular mechanism for neural development, we focused on bHLH genes and characterized their functions. Since the membrane protein Notch, which is known to maintain neural precursors, induced expression of the inhibitory bHLH genes Hes1 and Hes5, functions of these bHLH genes in neural precursor cells were first determined by expressing the active form of Notch in cells prepared from Hes1-null, Hes5-null, and Hes1-Hes5 double-null mouse embryos. Whereas Notch still inhibited differentiation in the absence of either Hes1 or Hes5, it did not in the absence of both Hes1 and Hes5 as essential Notch effectors. Thus, Notch-Hes pathway plays an important role in maintenance of neural precursor cells at early stages of development. At later stages of neural development, Hes5 was expressed by differentiating glial cells. Misexpression of Hes5 in the developing retina specifically induced gliogenesis and conversely glial cell number was reduced in Hes5-deficient retina. In contrast, Hes1 inhibited both neuronal and glial cell development and maintained neural precursor cells even at later stages. Neuronal bHLH genes such as Math3 and Mash1 promoted neurogenesis but inhibited gliogenesis. Thus, bHLH genes regulate all the cell fate, remaining as precursors (Hes1, Hes5) and differentiating into neurons (Math3, Mash1) or glial cells (Hes5), and the balance of these bHLH genes may be important for the timing of differentiation and the ratios of neurons versus glial cells.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Takebayashi,K. et al.: "Conversion of ectoderm into a neural fate by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal"EMBO J.. 16. 384-395 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kageyama,R. et al.: "Helix-loop-helix factors in growth and differentiation of the nervous system"Curr.Op.Genet.Dev.. 7. 659-665 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsuda,H. et al.: "Structure and promoter analysis of Math3 gene atonal : neural-specific expression by dual promoter elements"J.Biol.Chem.. 273. 6327-6333 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohtsuka,T., et al.: "Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation"EMBO J.. 18. 2196-2207 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Isaka,F., et al.: "Ectopic expression of the bHLH gene Math1 disturbs neural development"Eur.J.Neurosci.. 11. 2582-2588 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tomita,K., et al.: "The bHLH gene Hes1 is essential for expansion of early T cell precursors"Genes & Dev.. 13. 1203-1210 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takebayashi, K.et al.: "Conversion of ectoderm into a neural fate by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal."EMBO J.. 16. 384-395 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kageyama, R.et al.: "Helix-loop-helix factors in growth and differentiation of the nervous system."Curr. Op. Genet. Dev.. 7. 659-665 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsuda, H.et al.: "Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal : neural-specific expression by dual promoter elements."J. Biol. Chem.. 273. 6327-6333 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohtsuka, T.,et al.: "Hesl and Hes5 as Notch effectors in mammalian neuronal differentiation."EMBO J.. 18. 2196-2207 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Isaka, F.,et al.: "Ectopic expression of the bHLH gene Math1 disturbs neural development."Eur. J. Neurosci.. 11. 2582-2588 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tomita, K.,et al.: "The bHLH gene Hes1 is essential for expansion of early T cell precursors."Genes 」ヲ Dev.. 13. 1203-1210 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohtsuka T.et al.: "Hesl and Hes5 as Notch effectors in mammalian neuronal differentiation"EMBO J.. 18. 2196-2207 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Isaka F.et al.: "Ectopic expression of the bHLH gene Mathl disturbs neural development"Eur.J. Neurosci.. 11. 2582-2588 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tomita K.et al.: "The bHLH gene Hesl is essential for expansion of early T cell precursors"Genes & Dev.. 13. 1203-1210 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Konishi Y.et al.: "Transcriptional regulation of mouse type 1 inositol 1.4.5-triphosphate receptor gene by NeuroD-related factor"J. Neurochem.. 72. 1717-1724 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakamura Y.et al.: "The bHLH gene Hesl as a repressor of the neuronal commitment of CNS stem cells"J. Neurosci.. 20. 283-293 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Jensen J.et al.: "Control of endodermal endocrine development by HES-1"Nature Genet.. 24. 36-44 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ohtsuka,T., et al.: "Hesl and Hes5 as Notch effectors in mammalian neuronal differentiation." EMBO J.(発表予定). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tsuda,H., et al.: "Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal: neural-specific expression by dual promoter elements." J.Biol.Chem.273. 6327-6333 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishimura,M., et al.: "Structure, chromosomal locus and promoter of mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split." Genomics. 49. 69-75 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohtsuka,T., et al.: "Regulated expression of neurogenic basic helix-loop-helix transcription factors during differentiation of the immortalized neuronal progenitor cell line HC2S2 into neurons." Cell Tissue Res.293. 23-29 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Konishi,Y., et al.: "Transcriptional regulation of mouse type 1 inositol 1,4,5-triphosphate receptor gene by Neuro D-related factor." J.Neurochem.(発表予定). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takebayashi,K.et al.: "Conversion of ectoderm into a neural fate by ATH-3,a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal." EMBO J.16. 384-395 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsue,M.et al.: "Helix-loop-helix-type transcription factor(HES-1)is expressed in osteoblastic cells,suppressed by 1,25(OH)_2 vitamin D_3,and modulates 1,25(OH)_2 vitamin D_3 enhancement of osteopontin gene expression." Bone. 20. 329-334 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kageyama,R.et al.: "Helix-loop-helix factors in growth and differentiation of the nervous system." Curr.Opin.Genet.Dev.7. 659-665 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kageyama,R.et al.: "bHLH transcription factors and mammalian neuronal differentiation." Int.J.Biochem. Cell Biol.(発表予定). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsuda,H.et al.: "Structure and promoter analysis of Math3 gene,a mouse homolog of Drosophila proneural gene atonal : neural-specific expression by dual promoter elements." J.Biol.Chem.(発表予定). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nishimura,M.et al.: "Structure,chromosomal locus and promoter of mouse Hes2 gene,a homologue of Drosophila hairy and Enhancer of split." Genomics. (発表予定). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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