Life without Huntington: Normal differentiation into functional neurons

Huntington disease (HD) is a neurodegenerative disorder associated with pol yglutamine expansion in a recently identified protein, huntingtin. Huntingt in is widely expressed and plays a crucial role in development, because gen e-targeted HD-/- mouse embryos die early in embryogenesis. To analyze the f unction of normal huntingtin, we have generated HD-/- embryonic stem (ES) c ells and used an in vitro model of ES cell differentiation to analyze their ability to develop into neuronal cells. Expression analysis of wild-type E S cells revealed that huntingtin is expressed at all stages during ES cell differentiation with high expression in neurons. Expression levels increase d with the maturation of differentiating neurons, demonstrating that expres sion of huntingtin is developmentally regulated in cell culture and resembl es the pattern of expression observed in differentiating neurons in the mou se brain. It is interesting that HD-/- ES cells could differentiate into ma ture postmitotic neurons that expressed functional voltage- and neurotransm ittergated ion channels. Moreover, both excitatory and inhibitory spontaneo us postsynaptic currents were observed, indicating the establishment of fun ctional synapses in the absence of huntingtin. These results demonstrate th at huntingtin is not required for the generation of functional neurons with features characteristic of postmitotic neurons in the developing mouse bra in.