A key role for p60-Katanin in axon navigation is conditioned by the tubulin polyglutamylase TTLL6

The microtubule cytoskeleton is a major driving force of neuronal circuit development. Fine-tuned remodelling of this network by selective activation of microtubule-regulating proteins, including microtubule severers, emerged as a central process in neuronal wiring. Tubulin posttranslational modifications control both microtubule properties and the activities of their interacting proteins. However, whether and how tubulin posttranslational modifications may contribute to neuronal connectivity has not yet been addressed. During zebrafish embryogenesis, we show that the microtubule severers p60-katanin and spastin play specific roles in axon guidance and identify a key role for tubulin polyglutamylation in their functional specificity. Furthermore, our work reveals that polyglutamylases with undistinguishable activities in vitro, TTLL6 and TTLL11, play exclusive roles in axon navigation by selectively tuning p60-katanin and spastin activities. We confirm the selectivity of TTLL11 towards spastin activation in mammalian cortical neurons and establish its relevance in preventing axonal degeneration triggered by spastin haploinsufficiency. Our work thus provides mechanistic insight on the control of microtubule-driven neuronal development and homeostasis, and opens novel avenues for developing therapeutic strategies in spastin-associated hereditary spastic paraplegia.