Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

• Published in: Nature communications 2015-06, Vol.6 (1), p.7246-7246, Article 7246
• Main Authors: Deloulme, Jean-Christophe, Gory-Fauré, Sylvie, Mauconduit, Franck, Chauvet, Sophie, Jonckheere, Julie, Boulan, Benoit, Mire, Erik, Xue, Jing, Jany, Marion, Maucler, Caroline, Deparis, Agathe A., Montigon, Olivier, Daoust, Alexia, Barbier, Emmanuel L., Bosc, Christophe, Deglon, Nicole, Brocard, Jacques, Denarier, Eric, Le Brun, Isabelle, Pernet-Gallay, Karin, Vilgrain, Isabelle, Robinson, Phillip J., Lahrech, Hana, Mann, Fanny, Andrieux, Annie
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/28; 14/35; 59; 59/36; 59/57; 631/378/2571; 631/45/612/1228; 631/80/128/1653; 631/80/86; 64/60; 82/51; Animals; Axons - metabolism; Brain - metabolism; Brain - pathology; Development Biology; Diffusion Tensor Imaging; Fornix, Brain - embryology; Fornix, Brain - metabolism; Fornix, Brain - pathology; Glycoproteins - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Life Sciences; Magnetic Resonance Imaging; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Microtubule-Associated Proteins - genetics; multidisciplinary; Neural Pathways - embryology; Neural Pathways - metabolism; Neurites - metabolism; Neuroanatomical Tract-Tracing Techniques; Neurobiology; Neurons - metabolism; Neurons and Cognition; Organ Size; Science; Science (multidisciplinary); src Homology Domains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8246

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts. Loss of the structural microtubule-associated protein 6 (MAP6) leads to neuronal differentiation defects that are independent of MAP6’s microtubule-binding properties. Here the authors establish a functional link between MAP6 and Semaphorin 3E signalling for proper formation of the fornix of the brain.