Dynamic modulation of membrane tension and mechanosensitive ion channel activity steers the nerve growth cone

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The precise wiring of the developing nervous system depends on the path-finding abilities of the neuronal growth cone (GC), a highly dynamic sensory structure at the tip of growing axons. Growth cone turning is a fundamental behavior during axon guidance, yet its underlying mechanisms are incompletely understood. The GC membrane contains mechanosensitive ion channels (MSC) that are proposed to sense changes in membrane tension and transduce these changes into electrical signals. The objective of this program is to understand how the GC cytoskeleton, membrane tension, and the activity of mechanosensitive ion channels interact together to steer the growth cone. We hypothesize that in response to a gradient of guidance cues, GC turning is induced by an asymmetrical rigidification of the cytoskeleton, which alters the distribution of tension forces across the GC membrane and leads to an asymmetry in MSC activity. We will use a combination of molecular and cellular biology, live fluorescence imaging and pharmacology to examine the spatio-temporal distribution of the cytoskeleton and MSC activity across the GC membrane during its turning. These experiments will shed light onto a novel aspect of growth cone guidance. This combination of experimental approaches is unique and novel. It will enable us to further our understanding of GC steering. Elucidating how MSCs and membrane tension are involved in guided axonal growth will provide important insights into the intricate signaling mechanisms underlying neuronal wiring, which is fundamental for normal brain development and functional recovery after injury and diseases.