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

Abstract

AbstractSelective interplay between microtubules and their regulatory proteins emerged as major regulator of neuronal circuit development. However, how microtubule posttranslational modifications influence this interplay to govern axon guidance and targeting remains elusive. Using loss-of-function and rescue experiments during zebrafish development, we show that the microtubule-severing enzyme p60-Katanin controls motor axon pathfinding and larval mobility in a dose-dependent manner, and plays non-overlapping roles with the related protein Spastin in these processes. Notably, we uncover the tubulin glutamylase TTLL6 as a selective and key regulator of p60-Katanin activity during axon navigation. In contrast, our study demonstrates that, although critical for motor circuit wiring, the highly similar glutamylase TTLL11 fails to influence p60-Katanin and to rescue the axon targeting errors associated with TTLL6 knockdown, which discloses the functional specificity of these long-chain glutamylases at a physiological level. Altogether, our work provides in vivo proofs of concept that the tubulin code acts in a highly selective manner to tune the activity of key microtubule-severers in neuronal circuit wiring of a vertebrate model.