Ari Carlo Sarfatis
Department of Stem Cell and Regenerative Biology and Center for Brain Science
Project Title: Targeted manipulation of growth cone molecular networks implicated in cerebral cortex circuit (re)generation.
Cortical projection neurons are integral to many of the most important capacities of neural circuitry, including sensation, motion, and higher-order cognition. These glutamatergic neurons cross extremely long distances -- up to 10,000s of times their cell body size! -- in order to connect remote neural networks. They enable, for example, direct communication between the two cerebral hemispheres or fine motor limb control via the spinal cord.
But how do growing projection neurons determine which path to take during development ? More specifically, how do the tips of growing axons -- called neuronal growth cones -- integrate extracellular guidance cues with their own neuronal identity to consistently find their downstream targets in a complex and changing environment ? How do growth cones make pathfinding decisions when their nucleus, which contains the DNA of the neuron, is so far away ?
Aiming to answer some of these questions, a pioneering technical approach newly developed by the Macklis lab combines cellular labeling, biochemical fractionation, and organelle-resolution flow cytometry to provide a privileged window onto the internal molecular state of growth cones. These experiments have already revealed subtype-specific subcellular enrichment of molecular networks regulating cue response, which might underlie semi-autonomous decision making at the growth cone level.
Since localized networks of protein and RNA at growth cones likely exert direct control over neural circuitry formation, my MSc project aims to develop versatile tools inspired by recent findings of the Macklis lab enabling 1) targeted molecular trafficking specifically to growth cones and 2) local manipulation of molecular networks present in growth cones.If successful, targeted subcellular molecular trafficking and manipulation at the growth cone level in cortical projection neurons might be both pivotal in furthering our basic understanding of nervous system development, as well as instrumental in providing new ways to manipulate neurons for potential future regenerative therapies, e.g. in the context of stroke, spinal cord injury or ALS.