Guidance of axonal pathfinding via nano-switches

Objective

Axon navigation is guided by spatial patterns of chemical and physical cues in the developing brain. After a damage, the pattern is lost. Axons do not have instructions to reach their target. Axon regeneration, if stimulated, occurs by chance. Unfortunately, current technologies do not allow us to control axon navigation decisions, and guided re-innervation is not possible in the central nervous system (CNS). The GAP project aims to fill this knowledge gap by modulating neuron mechanotransduction, in order to program axon pathfinding and to differentiate axon navigation decisions. Cells will be engineered to express magnetic nano-switches that can generate forces in specific nano/micro domains of specific neurons. Depending on the domain, the force triggers a different mechanotransduction pathway, resulting in axon elongation or axon retraction. The integration of the different outputs from different neurons can be used to re-shape the network. GAP will demonstrate the ability: i) to change navigation decisions (e.g., to guide axon elongation in the direction of a repelling cue or to disengage axon outgrowth mediated by an attracting cue); ii) to differentiate between different navigation decisions in a mixed neuronal population (e.g., excitatory versus inhibitory neurons); iii) to control axon navigation decisions in a living organism (e.g., promoting reinnervation of excitatory neurons in models of spinal cord injury). GAP would demonstrate the ability to control neural network remodeling which remains an unmet challenge for science.