Filopodia In Vitro and In Vivo

Abstract

Filopodia are dynamic cell surface protrusions used for cell motility, pathogen infection, and tissue development. The molecular mechanisms determining how and where filopodia grow and retract need to integrate mechanical forces and membrane curvature with extracellular signaling and the broader state of the cytoskeleton. The involved actin regulatory machinery nucleates, elongates, and bundles actin filaments separately from the underlying actin cortex. The refined membrane and actin geometry of filopodia, importance of tissue context, high spatiotemporal resolution required, and high degree of redundancy all limit current models. New technologies are improving opportunities for functional insight, with reconstitution of filopodia in vitro from purified components, endogenous genetic modification, inducible perturbation systems, and the study of filopodia in multicellular environments. In this review, we explore recent advances in conceptual models of how filopodia form, the molecules involved in this process, and our latest understanding of filopodia in vitro and in vivo. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 39 is October 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Fascin structural plasticity mediates flexible actin bundle construction

“…Our data imply that forces which deform fascin crosslinked bundles could alter their internal molecular structure and functional properties, for instance by rearranging the F-actin helix through twist-bend coupling 63,64 , as well as by modulating fascin’s conformational landscape. Additionally, while we find that the minimal two-component fascin / F-actin system recapitulates much of the previously described complexity of filopodia cores 8,11 , fascin collaborates with additional crosslinkers to build other classes of protrusions such as stereocilia 65,66 . One such crosslinker is plastin, whose conformational dynamics differ substantially from fascin’s 7,58,67 , suggesting multi-crosslinker networks may feature distinct architectures and functional properties.…”

“…Filopodia are localized at the leading edge of migrating cells, where they function as dynamic antennae that sense and respond to external cues that instruct cytoskeletal dynamics 8,10–14 . Physiologically, filopodia are necessary for axonal outgrowth and pathfinding, embryonic development, and wound healing 8,11,12,15–20 . Pathologically, they are prominently associated with enhanced migration of metastatic cancer cells 21–25 .…”

“…Here, we focus on co-linear actin filament (F-actin) assemblies with uniform polarity (hereafter referred to as “bundles”), which mediate the generation and maintenance of rod-like plasma membrane protrusions that are critical for hearing and balance (stereocilia), nutrient absorption (microvilli), and directed cell migration (filopodia) 5–8 . Filopodia are localized at the leading edge of migrating cells, where they function as dynamic antennae that sense and respond to external cues that instruct cytoskeletal dynamics 7,9,10 . Physiologically, filopodia are necessary for axonal outgrowth and pathfinding, embryonic development, and wound healing 7,9–14 .…”

Filopodial protrusion driven by density-dependent Ena–TOCA-1 interactions

“…Axonal growth cone navigation underlies accurate neuronal connectivity in the brain and is guided by chemical and mechanical cues that are transduced to the cytoskeletal machinery to enable movement and turning ( O'Connor et al, 1990 ; Koser et al, 2016 ). A key element in this navigation process is the protrusion of filopodia through the dynamic growth and shrinkage of long, unbranched bundles of actin filaments, controlled by actin regulators at the filopodium tip ( Mallavarapu and Mitchison, 1999 ; Applewhite et al, 2007 ; Blake and Gallop, 2023 ). In the axonal growth cone, stochastic protrusion of filopodia has roles in transient adhesion to surfaces and promotion of accurate movement ( O'Connor et al, 1990 ; Dwivedy et al, 2007 ).…”