Life without Huntingtin: Normal differentiation into functional neurons

Martina Metzler, Nansheng Chen, Cheryl D. Helgason, Rona K. Graham, Kerrie Nichol, Krista McCutcheon, Jamal Nasir, R. Keith Humphries, Lynn A. Raymond, Michael R. Hayden

    Research output: Contribution to journalArticle

    Abstract

    Huntington disease (HD) is a neurodegenerative disorder associated with polyglutamine expansion in a recently identified protein, huntingtin. Huntingtin is widely expressed and plays a crucial role in development, because gene-targeted HD-/- mouse embryos die early in embryogenesis. To analyze the function of normal huntingtin, we have generated HD-/- embryonic stem (ES) cells and used an in vitro model of ES cell differentiation to analyze their ability to develop into neuronal cells. Expression analysis of wild-type ES cells revealed that huntingtin is expressed at all stages during ES cell differentiation with high expression in neurons. Expression levels increased with the maturation of differentiating neurons, demonstrating that expression of huntingtin is developmentally regulated in cell culture and resembles the pattern of expression observed in differentiating neurons in the mouse brain. It is interesting that HD-/- ES cells could differentiate into mature postmitotic neurons that expressed functional voltage- and neurotransmitter-gated ion channels. Moreover, both excitatory and inhibitory spontaneous postsynaptic currents were observed, indicating the establishment of functional synapses in the absence of huntingtin. These results demonstrate that huntingtin is not required for the generation of functional neurons with features characteristic of postmitotic neurons in the developing mouse brain.
    Original languageEnglish
    Pages (from-to)1009-1018
    Number of pages10
    JournalJournal of Neurochemistry
    Volume72
    DOIs
    Publication statusPublished - 1 Mar 1999

    Fingerprint

    Neurons
    Embryonic Stem Cells
    Stem cells
    Huntington Disease
    Cell Differentiation
    Brain
    Inhibitory Postsynaptic Potentials
    Aptitude
    Ion Channels
    Cell culture
    Neurodegenerative Diseases
    Synapses
    Embryonic Development
    Neurotransmitter Agents
    Embryonic Structures
    Cell Culture Techniques
    Genes
    Electric potential
    Proteins

    Keywords

    • Huntingtin-Knockout-Embryonic stem cells
    • Ion channels
    • Neurogenesis
    • Synaptic transmission

    Cite this

    Metzler, M., Chen, N., Helgason, C. D., Graham, R. K., Nichol, K., McCutcheon, K., ... Hayden, M. R. (1999). Life without Huntingtin: Normal differentiation into functional neurons. Journal of Neurochemistry, 72, 1009-1018. https://doi.org/10.1046/j.1471-4159.1999.0721009.x
    Metzler, Martina ; Chen, Nansheng ; Helgason, Cheryl D. ; Graham, Rona K. ; Nichol, Kerrie ; McCutcheon, Krista ; Nasir, Jamal ; Humphries, R. Keith ; Raymond, Lynn A. ; Hayden, Michael R. / Life without Huntingtin: Normal differentiation into functional neurons. In: Journal of Neurochemistry. 1999 ; Vol. 72. pp. 1009-1018.
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    Metzler, M, Chen, N, Helgason, CD, Graham, RK, Nichol, K, McCutcheon, K, Nasir, J, Humphries, RK, Raymond, LA & Hayden, MR 1999, 'Life without Huntingtin: Normal differentiation into functional neurons', Journal of Neurochemistry, vol. 72, pp. 1009-1018. https://doi.org/10.1046/j.1471-4159.1999.0721009.x

    Life without Huntingtin: Normal differentiation into functional neurons. / Metzler, Martina; Chen, Nansheng; Helgason, Cheryl D.; Graham, Rona K.; Nichol, Kerrie; McCutcheon, Krista; Nasir, Jamal; Humphries, R. Keith; Raymond, Lynn A.; Hayden, Michael R.

    In: Journal of Neurochemistry, Vol. 72, 01.03.1999, p. 1009-1018.

    Research output: Contribution to journalArticle

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    Metzler M, Chen N, Helgason CD, Graham RK, Nichol K, McCutcheon K et al. Life without Huntingtin: Normal differentiation into functional neurons. Journal of Neurochemistry. 1999 Mar 1;72:1009-1018. https://doi.org/10.1046/j.1471-4159.1999.0721009.x