Neurons lacking huntingtin differentially colonize brain and survive in chimeric mice

To determine whether neurons lacking huntingtin can participate in developm ent and survive in postnatal brain, we used two approaches in an effort to create mice consisting of wildtype cells and cells without huntingtin. In o ne approach, chimeras were created by aggregating the 4-8 cell embryos from matings of Hdh (+/-) mice with wild-type 4-8 cell embryos. No chimeric off spring that possessed homozygous Hdh (-/-) cells were obtained thereby, alt hough statistical considerations suggest that such chimeras should have bee n created. By contrast, Hdh (-/-) ES cells injected into blastocysts yielde d offspring that were born and in adulthood were found to have Hdh (-/-) ne urons throughout brain. The Hdh (-/-) cells were, however, 5-10 times more common in hypothalamus, midbrain, and hindbrain than in telencephalon and t halamus. Chimeric animals tended to be smaller than wild-type littermates, and chimeric mice rich in Hdh (-/-) cells tended to show motor abnormalitie s. Nonetheless, no brain malformations or pathologies were evident. The apparent failure of aggregation chimeras possessing Hdh (-/-) cells to survive to birth is likely attributable to the previously demonstrated crit ical role of huntingtin in extraembryonic membranes. That Hdh (-/-) cells i n chimeric mice created by blastocyst injection are under-represented in ad ult telencephalon and thalamus implies a role for huntingtin in the develop ment of these regions, whereas the neurological dysfunction in brains enric hed in Hdh (-/-) cells suggests a role for huntingtin in adult brain. Nonet heless, the lengthy survival of Hdh (-/-) cells in adult chimeric mice indi cates that individual neurons in many brain regions do not require huntingt in to participate in normal brain development and to survive.