Actomyosin Contractility and Actin Polymerization Explain Dynamic Behavior of Dendritic Filopodia

Abstract

Dendritic filopodia are actin-filled highly dynamic subcellular structures that sprout densely on neuronal dendrites during early brain development. A fraction of filopodia undergo a transition to dendritic spines that later mature into synapses - a process crucial for memory formation and learning, and deficient in neurodevelopmental and neurodegenerative diseases. The dynamics of dendritic filopodia is also different from that of conventional filopodia: the former exhibit sustained length fluctuations and cease their dynamic behavior after transition into spines. While actin retrograde flow in dendritic filopodia was measured previously, there has been no detailed theoretical description of how the flow is maintained and how length oscillations are sustained in dendritic filopodia. We apply mathematical modeling and experimental techniques to dissect and analyze the components of actin-based motility in dendritic filopodia, and suggest its role in the subsequent transition into the spine shape. The simulations demonstrate that the movement of actin network influenced by myosin contractility and viscous shear stresses lead to the myosin build up at the base of the filopodium and its consequent retraction. When myosin is inactive, the filopodium grows with the rate of actin polymerization. However, when myosin is active, the processes of polymerization at the tip, and cytoskeletal contraction due to myosin, and resistance to the flow out of the filopod at the base, conspire to produce an actin flow gradient along the filopodial axis. We have measured average rates of growth and retraction of filopodia in cultured hippocampal neurons using a custom tip-tracking algorithm. The simulated length fluctuations and actin retrograde flow compare well with the experimental data. We estimate the resistive force at the base of filopodia necessary to maintain the pattern of growth and shrinking and suggest new experiments to test the proposed mechanism.