Repurposing the Chromosome Segregation Machinery to Build and Regenerate Neural Circuits

The brain is a precisely wired network of billions of neurons. Two highly specialized compartments extending from the neuronal cell body - dendrites, receiving input signals, and axons transmitting them - interconnect to form functional circuits. During development, actin and microtubule cytoskeletal remodeling drives extension of dendrites and axons to establish accurate synaptic interconnections. Neuronal-cytoskeletal dysfunction is linked to neurological disorders, age-related cognitive decline, and neurodegeneration. Despite this intimate relationship between the cytoskeleton and brain wiring, the molecular mechanisms that link cytoskeletal restructuring to morphological transformations required to form neural circuits are poorly understood. My research has identified that, kinetochore proteins, that tether DNA to spindle microtubules during chromosome segregation, are repurposed as cytoskeletal regulators in dendrites and axons of non-dividing neurons to build and regenerate neural circuits. This proposal aims to elucidate how kinetochore components act beyond their classical cell division role, and interact with the neuronal cytoskeleton and subcellular structures to 1) ensure accurate dendrite branching 2) direct synapse formation, and 3) contribute to axon regeneration, using the developing nervous system of C.elegans as a discovery tool. Furthermore, I will extend key discoveries to complex vertebrate neural circuits and model human disease-linked mutations in in vitro mammalian systems.