title: The GSK3-MAP1B pathway controls neurite branching and microtubule dynamics.
abstract: The microtubule-associated protein MAP1B plays a key role in axon regeneration. We investigated the role of GSK3-mediated MAP1B phosphorylation in local fine-tuning of neurite branching and the underlying microtubule (MT) dynamics. In wildtype adult dorsal root ganglia (DRG) neurons, MAP1B phosphorylation is locally reduced at branching points, and branching dynamics from growth cones and distal neurite shafts is increased upon GSK3 inhibition. While map1b-/- neurites, that display increased branching, are not affected by GSK3 inhibition, transfection of map1b-/- neurons with full-length map1b-cDNA restores the wildtype branching phenotype, demonstrating that MAP1B is a key effector downstream of GSK3. Experiments in mutant mice lacking tyrosinated MTs indicate a preferential association of phospho-MAP1B with tyrosinated MTs. Interestingly, inhibition of GSK3-mediated MAP1B phosphorylation in map1b-cDNA-transfected fibroblasts protects both tyrosinated and acetylated MTs from nocodazole-induced depolymerization, while detyrosinated MTs are less abundant in the presence of MAP1B. Our data thus provide new insight into the molecular link between GSK3, MAP1B, neurite branching and MT stability regulation. We suggest that, at branching points, MAP1B undergoes a fine regulation of both its phosphorylation and sub-cellular amounts, in order to modulate the local balance between acetylated, detyrosinated, and tyrosinated microtubule pools.
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Monia
authors.initials: M
authors.lastname: Barnat
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Benassy
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Vincensini
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Soares
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Fassier
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, A-1030, Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Propst
authors.affiliation: INSERM, U836, F-38000 Grenoble, France; Univ. Grenoble Alpes, Grenoble Institut Neurosciences, F-38000 Grenoble, France; CEA, iRTSV, F-38000 Grenoble, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Andrieux
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France.
authors.forename: Ysander
authors.initials: Y
authors.lastname: von Boxberg
authors.affiliation: Neuroscience Paris Seine, CNRS UMR 8246, 7 Quai St Bernard, 75005 Paris, France; INSERM U1130, 7 Quai St Bernard, 75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UPMC UM 119, Paris, France. Electronic address: fatiha.nothias@upmc.fr.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Nothias
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis; D010766:Phosphorylation
chemical_list: D008869:Microtubule-Associated Proteins; D038362:Glycogen Synthase Kinase 3
keywords: Acetylated microtubules; COS-7 cells; Cell neurobiology; Cytoskeleton; DRG neurons; Detyrosinated microtubules; GSK signaling; MAP1B-knockout mice; Microtubule-associated protein 1B; Neurite outgrowth; Nocodazole; Regeneration; SB216763 GSK inhibitor; Tubulin–tyrosine ligase (TTL)-deficient mice; Tyrosinated microtubules