The polarized distribution of neuronal proteins to axons and dendrites relies on microtubule-binding proteins such as CRMP, directed motors such as the kinesin UNC-104 (Kif1A) and diffusion barriers such as ankyrin. The causative relationships among these molecules are unknown. We show here that Caenorhabditis elegans CRMP (UNC-33) acts early in neuronal development, together with ankyrin (UNC-44), to organize microtubule asymmetry and axon-dendrite sorting. In unc-33 and unc-44 mutants, axonal proteins were mislocalized to dendrites and vice versa, suggesting bidirectional failures of axon-dendrite identity. unc-44 directed UNC-33 localization to axons, where it was enriched in a region that resembled the axon initial segment. unc-33 and unc-44 were both required to establish the asymmetric dynamics of axonal and dendritic microtubules; in their absence, microtubules were disorganized, the axonal kinesin UNC-104 invaded dendrites, and inappropriate UNC-104 activity randomized axonal protein sorting. We suggest that UNC-44 and UNC-33 direct polarized sorting through their global effects on neuronal microtubule organization.
Bibliographical noteFunding Information:
We thank C. Ghenoiu, P. Nurse, Y. Saheki, S. Shaham, M. Tsunozaki, M. Heiman, A. Kelly, T. Starich and members of our labs for advice and comments on the manuscript, C. Janke (Institut Curie) and B. Edde (Universite Pierre et Marie Curie) for antibodies, and Y. Saheki (Rockefeller University) and the Caenorhabditis Genetics Center for strains. C.I.B. and K.S. are Investigators of the Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute.