Tubulin glutamylation regulates axon guidance via the selective tuning of microtubule-severing enzymes
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-severing enzymes, has 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. Here we show that the microtubule-severing proteins p60-katanin and spastin play specific roles in axon guidance during zebrafish embryogenesis 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 motor circuit wiring by selectively tuning p60-katanin- and spastin-driven motor axon guidance. We confirm the selectivity of TTLL11 towards spastin regulation in mouse cortical neurons and establish its relevance in preventing axonal degeneration triggered by spastin haploinsufficiency. Our work thus provides mechanistic insight into the control of microtubule-driven neuronal development and homeostasis and opens new avenues for developing therapeutic strategies in spastin-associated hereditary spastic paraplegia.
Authors
- Cécile Haumaître (ORCID: https://orcid.org/0000-0003-3526-7832)
- Daniel Ten Martín
- Maria M. Magiera (ORCID: https://orcid.org/0000-0003-4847-3053)
- Juliette Vougny (ORCID: https://orcid.org/0000-0002-7361-8405)
- Jamïlé Hazan (ORCID: https://orcid.org/0000-0001-8119-0325)
- Coralie Fassier (ORCID: https://orcid.org/0000-0003-3015-4281)
- Nicolas Jardin (ORCID: https://orcid.org/0000-0003-1216-2894)
- Matthias Kneussel (ORCID: https://orcid.org/0000-0003-4900-366X)
- Xavier Nicol (ORCID: https://orcid.org/0000-0002-0310-8047)
- Carsten Janke (ORCID: https://orcid.org/0000-0001-7053-2000)
- François Giudicelli (ORCID: https://orcid.org/0000-0003-1320-2958)
- Laura Lebrun (ORCID: https://orcid.org/0000-0002-9193-1534)
- Laïla Gasmi (ORCID: https://orcid.org/0009-0001-8560-7877)
- Véronique Henriot
- Naomi Berbée
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut de la Vision (FR)
- Inserm (FR)
- Universität Hamburg (DE)
- Délégation Paris 7 (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Sorbonne Université (FR)
- Institut de Biologie Paris-Seine (FR)
- University Medical Center Hamburg-Eppendorf (DE)
- Centre Interdisciplinaire de Recherche en Biologie (FR)
- Institut de Biologie de l'École Normale Supérieure (FR)
- Amsterdam University Medical Centers (NL)
- Neurosciences Paris-Seine (FR)
- Institut Curie (FR)
- University of Amsterdam (NL)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1038/s44318-024-00307-x
- Citations
- 6
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- Sorbonne Université