Microtubules (MTs) act as tracks upon which molecular motors, such as kinesins and dyneins, travel to transport essential materials throughout cells. However, the mechanisms that regulate MT structure and motor functions to ensure that diverse cargos are appropriately delivered to particular regions or organelles within cells is not completely understood. In neurons, regulation of MT-based transport may be especially important because they extend elongated axons and dendrites. Although all MTs are made by assembly of alpha and beta tubulins, they are not uniform. The Tubulin Code hypothesis suggests that MTs can be specialized by incorporating different alpha and beta tubulins, as well as addition of reversible post-translational modifications (PTMs) such as glutamylation (addition of glutamate side chains to alpha or beta tubulin C-terminal tails). We previously found that glutamylases that add glutamylation to MTs (TTLL-4, TTLL-5, and TTLL-11) and a deglutamylase that reduces glutamylation (CCPP-1) influence MT structure and the activity of particular motors in sensory neuronal cilia in a cell-specific manner. Particular tubulins are also essential for regulating the structure of MTs in neuronal sensory cilia. Therefore, the MT tracks themselves encode information that regulates their own structure and stability, as well as the function of kinesin motors. Non-motor microtubule-associated proteins (MAPs) act as another mechanism to regulate the MT cytoskeleton, but the function of many MAPs is not yet known. MT binding of some MAPs, such as mammalian Tau, has been found to be sensitive to MT glutamylation in vitro, suggesting that these two layers of MT regulation may interact. To understand the genetic interactions of MAPs and the Tubulin Code, we observed the localization of fluorescently-tagged MAPs, such as the C. elegans Tau homolog PTL-1 and the DCX family member/RP1L1 homolog F27C1.13, combined with mutations that disrupt particular tubulin genes or regulators of MT glutamylation. Both Tubulin Code PTMs and MAPs are involved in neurodegenerative diseases in humans. Mutation of a human
ccpp-1 homolog is associated with infantile-onset neurodegeneration, Tau is implicated in Alzheimer's Disease and other Tauopathies, and mutation of RP1L1 is associated with occult macular dystrophy, resulting in progressive blindness. Both PTL-1 and F27C1.13 were expressed in ciliated sensory neurons, suggesting that C. elegans might be used to model the human diseases associated with these genes. Our results support the hypothesis that PTMs and MAPs are essential cytoskeletal regulators that act in concert to regulate and specialize neuronal MTs.