ALTERED MICROTUBULE ORGANIZATION IN SMALL-CALIBER AXONS OF MICE LACKING TAU-PROTEIN

THE tau gene encodes a protein (Tau) that is a major neuronal microtub ule-associated protein localized mostly in axons(1-4). It has microtub ule-binding and tubulin-polymerizing activity in vitro(3,4) and is tho ught to make short crossbridges between axonal microtuhules(5,6). Furt her, tau-transfected non-neuronal cells extend long axon-like processe s in which microtubule bundles resembling those in axons are formed(6- 8). In contrast, tau antisense oligonucleotides selectively suppress a xonal elongation in cultured neurons(9,10). Thus tau is thought to be essential for neuronal cell morphogenesis, especially axonal elongatio n and maintenance. To test this hypothesis, we used gene targeting to produce mice lacking the tau gene. We show that the nervous system of tau-deficient mice appears to be normal immunohistologically. Furtherm ore, axonal elongation is not affected in cultured neurons. But in som e small-calibre axons, microtubule stability is decreased and microtub ule organization is significantly changed. We observed an increase in microtubule-associated protein 1A which may compensate for the functio ns of tau in large-calibre axons. Our results argue against the sugges ted role of tau in axonal elongation but confirm that it is crucial in the stabilization and organization of axonal microtubules in a certai n type of axon.