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Features of a mouse model of early-stage Huntington disease indicate that the model is reasonably accurate. An amino-terminal fragment of huntingtin, detected by western blot, is consistent with an initial pathogenic processing event and nuclear and extranuclear polyglutamine aggregates form selectively within striatal neurons. Further analysis of the model implies an extranuclear mechanism of neuronal dysfunction involving decreased uptake of glutamate by synaptic vesicles.
Rational vector design is pivotal for successful human gene therapy and the application of high-throughput methods may provide a means for the efficient realization of vectors with desired properties. A method involving DNA shuffling represents a powerful new paradigm in this regard.
Each somite of the vertebrate embryonic body axis is subdivided into a rostral and a caudal half. Using elegantly designed mouse genetic experiments, a recent paper provides insight into the mechanisms that select between these two fates. Remarkably, both states require Notch activity, but the signal is transduced by a different pathway in each half.
In model organisms, chemical mutagenesis provides a powerful alternative to natural, polygenic variation (for example, quantitative trait loci (QTLs)) for identifying functional pathways and complex disease genes. Despite recent progress in QTLs, we expect that mutagenesis will ultimately prove more effective because the prospects of gene identification are high and every gene affecting a trait is potentially a target.
