Lipid Raft-Mediated Regulation of Membrane Dynamics for Targeted Innervation (RaftedMembranes)

Brain function relies on a complex network of interconnected neurons that arises during development and remains grossly stable in adults. Unveiling how connectivity develops is crucial to understand brain function. Target innervation depends on precise responses of the growth cone, the tip of the growing axon, at choice points. In the visual system, the chiasma is a major choice point where subsets of retinal ganglion cells (RGCs) choose to project to distinct brain hemispheres depending on their localization. The molecular determinants shaping the response of RGCs in this choice point are known, but how the growth cone orchestrates its internal machinery to execute its precise choices is not understood. Moreover, the mechanisms confining cellular effectors, like membrane remodeling and exocytosis, that enable the exquisite directionality of the growth cone are elusive. Lipid rafts, specialized cholesterol- and sphingolipid-enriched domains of the membrane, are perfect candidates to link the intracellular signals generated by guidance cues and localize growth cone responses.

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This project aims to describe how lipid rafts orchestrate exocytosis and membrane dynamics in the growth cone, directing the connectivity of the nervous system.

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Using a systematic approach to visualize exocytotic events taking place in the growth cone with high resolution, local interference of the cell machinery to induce navigation defects in vivo with innovative tools, and a final step to engineer new innervations “a la carte” with local activation of membrane exocytosis, I will provide a mechanistic understanding of growth cone turning in the chiasma. This project will provide a global understanding of the cellular and molecular processes driving neuronal connectivity, and might grant new strategies to tackle neurodevelopmental disorders and axon regeneration.