HUMAN HUNTINGTIN DERIVED FROM YAC TRANSGENES COMPENSATES FOR LOSS OF MURINE HUNTINGTIN BY RESCUE OF THE EMBRYONIC LETHAL PHENOTYPE

Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in exon 1 of a novel gene. The HD protein (huntingtin) plays a critical role in early embryonic development since homozygous targeted disruption of the murine HD gene results in embryonic lethality by da y 7.5. To rescue this phenotype by transgene based huntingtin expressi on it is therefore essential to express the protein early enough in de velopment in the appropriate cells. Since YAC based transgenes are kno wn to be regulated in an appropriate temporal and tissue-specific mann er, we sought to rescue the embryonic lethality by breeding YAC transg enic mice expressing human huntingtin with mice heterozygous for the t argeted disruption. We generated viable offspring homozygous for the d isrupted murine HD gene but expressing human huntingtin derived from t he YAC. This result clearly shows that YAC transgene based expression of huntingtin occurs prior to 7.5 days gestation. Additionally, we sho w that human huntingtin expression in YAC transgenic mice follows an i dentical tissue distribution and subcellular localisation pattern as t hat of the murine endogenous protein and that expression levels of 2-3 times endogenous can be achieved. This shows that human huntingtin un der the influence of its native promoter, despite differences to the m urine protein, is functional in a murine background and can compensate for loss of the murine protein. These results show that YAC transgeni c approaches are a particularly promising route to producing an animal model for disorders associated with CAG expansion.