Developmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. Regulation of the cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a post-translational tubulin modification enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation-TTLL glutamylases vs. CCP deglutamylases-accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.

Department of Molecular Neurobiology Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Department of Molecular Neurogenetics Center for Molecular Neurobiology ZMNH University Medical Center Hamburg Eppendorf Hamburg Germany

Faculty of Sciences Charles University Prague Czech Republic

German Center for Neurodegenerative Diseases Munich Germany

German Centre for Cardiovascular Research Partner Site Munich Heart Alliance Munich Germany

Institut Curie Université PSL Orsay France

Institute of Neuronal Cell Biology Technical University of Munich Munich Germany

Institute of Pharmacology and Toxicology Technical University of Munich Munich Germany

Munich Cluster of Systems Neurology Munich Germany

Université Paris Saclay Orsay France

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