Defects in axonal elongation and neuronal migration in mice with disruptedtau and map1b genes

Tau and MAP1B are the main members of neuronal microtubule-associated prote ins (MAPs), the functions of which have remained obscure because of a putat ive functional redundancy (Harada, A., K. Oguchi. S. Okabe, J, Kuno, S. Ter ada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 199 4. Nature 369:488-491; Takei, Y., S. Kondo, A. Harada, S. Inomata, T. Noda, and N. Hirokawa, 1997. J. Cell Biol. 137:1615-1626). To unmask the role of these proteins, we generated double-knockout mice with disrupted tan and m ap1b genes and compared their phenotypes with those of single-knockout mice . In the analysis of mice with a genetic background of predominantly C57Bl/ 6J a hypoplastic commissural axon tract and disorganized neuronal layering were observed in the brains of the tau +/+map1b-/- mice. These phenotypes a re markedly more severe in tau-/-map1b-/- double mutants, indicating that t au and MAP1B act in a synergistic fashion. Primary cultures of hippocampal neurons from tau-/-map1b-/- mice showed inhibited axonal elongation. In the se cells, a generation of new axons via bundling of microtubules at the nec k of the growth cones appeared to be disturbed. Cultured cerebellar neurons from tau-/-map1b-/- mice showed delayed neuronal migration concomitant wit h suppressed neurite elongation. These findings indicate the cooperative fu nctions of tau and MAP1B in vivo in axonal elongation and neuronal migratio n as regulators of microtubule organization.