Microtubule lattice renewal organizes the neuron – MicRON

A unique cytoskeletal architecture allows neurons to establish a complex and polarized arborization, and to maintain it for decades while ensuring the adaptation necessary for cognitive processes. Microtubules are dynamic polymers of tubulin that form tracks for the long-range transport of neuronal components and maintain a fine balance between stability and plasticity. Microtubules grow and shrink from one of their tips, but we now know that they can also be renewed by directly exchanging tubulin within their assembled lattice. Our project focuses on the existence and role of this in-lattice renewal within the stable microtubule arrays of neurons, as it is likely to be a significant mechanism that allows for progressive turnover without loss of the transport tracks. Our consortium brings together two renowned teams, one for the study of the neuronal cytoskeleton, and the other for the discovery of microtubule self-repair and its molecular mechanisms. We are currently developing optimized cellular micro-manipulation and nanoscopy approaches to visualize for the first time the microtubule lattice renewal at the structural scale within neurons. We will map the organization of microtubule turnover at multiple scales during neuronal development and dissect its regulation by microtubule-associated proteins and motor proteins. We will address the functional relevance of lattice renewal by focusing on the fundamental event neuronal polarity emergence. We hypothesize that the specification of a single axon from undifferentiated neurites is driven by a feedback loop centered on microtubule lattice damage and renewal that we will probe using innovative cell manipulation approaches. Thanks to its combination of new ideas and new techniques, this project is poised to reveal fundamental insights into neuronal morphogenesis and the mechanisms of cell polarity.