INCREASED APOPTOSIS AND EARLY EMBRYONIC LETHALITY IN MICE NULLIZYGOUSFOR THE HUNTINGTONS-DISEASE GENE HOMOLOG

The expansion of CAG triplet repeats in the translated region of the h uman HD gene, encoding a protein (huntingtin) of unknown function, is a dominant mutation leading to manifestation of Huntington's disease. Targeted disruption of the homologous mouse gene (Hdh), to examine the normal role of huntingtin, shows that this protein is functionally in dispensable, since nullizygous embryos become developmentally retarded and disorganized, and die between days 8.5 and 10.5 of gestation. Bas ed on the observation that the level of the regionalized apoptotic cel l death in the embryonic ectoderm, a layer expressing the Hdh gene, is much higher than normal in the null mutants, we propose that huntingt in is involved in processes counterbalancing the operation of an apopt otic pathway.