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Life Without Huntingtin
Author(s) -
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.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0721009.x
Subject(s) - huntingtin , biology , neuroscience , chemistry , genetics , gene , mutant
: Huntington disease (HD) is a neurodegenerative disorderassociated with polyglutamine expansion in a recently identified protein,huntingtin. Huntingtin is widely expressed and plays a crucial role indevelopment, because gene‐targeted HD ‐/‐ mouse embryos die early inembryogenesis. To analyze the function of normal huntingtin, we have generatedHD ‐/‐ embryonic stem (ES) cells and used an in vitro model of EScell differentiation to analyze their ability to develop into neuronal cells.Expression analysis of wild‐type ES cells revealed that huntingtin isexpressed at all stages during ES cell differentiation with high expression inneurons. Expression levels increased with the maturation of differentiatingneurons, demonstrating that expression of huntingtin is developmentallyregulated in cell culture and resembles the pattern of expression observed indifferentiating neurons in the mouse brain. It is interesting thatHD ‐/‐ ES cells could differentiate into mature postmitotic neurons that expressed functional voltage‐ and neurotransmittergated 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.