| Huntingtin (htt), the protein encoded by the Huntington's disease gene (HD), contains a polymorphic stretch of glutamines (polyQ) and a proline-rich region (PRR) near its amino terminus. When the polyQ stretch is expanded beyond 37Q, HD results. To determine the contribution of the polyQ stretch and the PRR to normal htt function, I generated two separate mouse mutants by gene targeting in embryonic stem cells. The first contains a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (Hdh DeltaQ), and the second mouse mutant lacks the PRR (HdhDeltaP). The polyglutamine stretch is not essential for htt function in embryogenesis, as Hdh(DeltaQ/DeltaQ) pups were obtained with normal Mendelian frequency from an Hdh(DeltaQ/+) intercross. Hdh(DeltaQ/DeltaQ mice display a subtly enhanced motor phenotype in vivo and fibroblasts derived from these mutants display elevated levels of ATP with cellular senescence in vitro. Taken altogether, these results suggest that htt's polyQ stretch is required for modulating longevity in culture, and support the hypothesis that htt's polyQ stretch may also regulate energy homeostasis. To assess the role of the polyQ stretch in the nonaffected htt allele in the context of HD, Hdh(DeltaQ/+) mice were crossed with Hdh(140Q/+) mice (a knock-in mouse model of HD expressing htt with a 140Q polyQ stretch). I show that eliminating the polyQ stretch in the non-affected htt allele in Hdh(140Q/DeltaQ) mice can alter mitochondrial function and dramatically improve phenotypes, including motor performance, learning, overall activity levels, and a marked reduction in aggregate formation. Further investigation will reveal if this phenomenon is a delay or amelioration of symptoms, as these mice are still young. In contrast to the Hdh(DeltaQ/DeltaQ) mice, mice homozygous for PRR deletion in htt, Hdh(DeltaP/DeltaP), were not born with Mendelian frequency; however, homozygous pups were obtained in the F4 generation. Therefore, the PRR is an essential htt domain in embryogenesis, but genetic modifiers exist that allow bypass of lethality in the appropriate background strain. This result suggests the possibility that undiscovered genes exist that have the ability to modify htt function in the developing mouse. |
