Expression of Normal and Mutant Huntingtin in the Developing Brain

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Abstract
Huntington’s disease (HD) is caused by a genetic mutation that results in a polyglutamine expansion in huntingtin. The time course of neuronal loss in the HD striatum and other affected brain regions before the onset of symptoms is unknown. To determine the potential influence of huntingtin on brain development, we examined its expression in the developing mouse and in human control and HD brain. By Western blot, huntingtin was detected throughout the adult mouse brain and at all stages of embryonic and postnatal brain development. The protein increased significantly between postnatal day 7 (P7) and P15, which marks a period of active neuronal differentiation and enhanced sensitivity to excitotoxic injury in the rodent striatum. Immunoreactivity was found in neurons throughout the brain and localized mostly to the somatodendritic cytoplasm and to axons in fiber bundles. Staining was variable in different groups of neurons and within the same cell population. In developing brain, huntingtin was limited primarily to neuronal perikarya. Increased immunoreactivity in large neurons followed the gradient of neurogenesis and appeared in the basal forebrain and brainstem by embryonic days 15–17, in regions of cortex by P0–P1, and in the striatum by P7. In human brain at midgestation (19–21 weeks), huntingtin was detected in all regions. The brain of a 10-week-old infant with the expanded HD allele expressed a higher molecular weight mutant form of huntingtin at levels comparable to those of the wild-type protein. Thus, mutant huntingtin is expressed before neuronal maturation is complete. Results suggest that huntingtin has an important constitutive role in neurons during brain development, that heterogeneity in neuronal expression of the protein is developmentally regulated, and that the intraneuronal distribution of huntingtin increases in parallel with neuronal maturation. The presence of mutant huntingtin in the immature HD brain raises the possibility that neurons may be affected during brain development and possibly in the postnatal period when vulnerability to excitotoxic injury is at its peak.