Myosin-X in neuronal development

Raines, Alexander

Myosin-X in neuronal development Public Deposited

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March 22, 2019

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Raines, Alexander
- Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum

Abstract

During development, our brains make trillions of connections that enable us to think, feel, and act. Forming these connections requires the precise generation, migration and differentiation of billions of neurons, which extend complex dendritic trees and an axon that can extend nearly a meter. Such complex cellular behaviors are generated by dynamic alterations to the cytoskeleton. Myosin-X (Myo10) is an unconventional myosin known for its functions in filopodia, thin actin-based protrusions thought to act as antennae for cell migration, axon outgrowth, and synapse formation. Myo10 can also directly link actin filaments to integrins and microtubules, interactions that are crucial for many stages in neuronal development. Furthermore, Myo10 can act as a cytoskeletal effector of the phosphoinositide 3-kinase (PI3K) pathway, positioning Myo10 to function downstream of many guidance cues and growth factors. The nervous system expresses a short isoform of Myo10 that lacks a functional motor domain. Termed headless Myo10, this isoform is thought to act as a dominant negative of full-length Myo10, but this hypothesis has not been tested and its function is unknown. Here I show that both full-length and headless Myo10 are expressed in the developing brain in germinal zones where neurons are generated and in neurons as they differentiate. I generated shRNA constructs to selectively knockdown headless and full-length Myo10 in cortical neuron cultures, which reveal opposing roles for Myo10 in axon outgrowth. Co-expression of headless and full-length Myo10 in COS-7 cells demonstrates that headless Myo10 can act as a negative regulator of full-length Myo10. Together, these results suggest that full-length Myo10 promotes axon outgrowth, while headless Myo10 antagonizes full-length Myo10 and limits protrusion. In addition, preliminary experiments and the expression pattern described here indicate that future studies may reveal functions of Myo10 in neurogenesis, neuronal migration and dendritic spine formation.

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