Actin dynamics in growth cone motility and navigation

Abstract

Motile growth cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that fill the growth cone leading margin (peripheral (P-) domain). Actin filament organization in growth cones is regulated by actin-binding proteins that control all aspects of filament assembly, turnover, interactions with other filaments and cytoplasmic components, and participation in producing mechanical forces. Actin filament polymerization drives protrusion of sensory filopodia and lamellipodia, and actin filament connections to the plasma membrane link the filament network to adhesive contacts of filopodia and lamellipodia with other surfaces. These contacts stabilize protrusions and transduce mechanical forces generated by actomyosin activity into traction that pulls an elongating axon along the path towards its target. Adhesive ligands and extrinsic guidance cues bind growth cone receptors and trigger signaling activities involving Rho GTPases, kinases, phosphatases, cyclic nucleotides and [Ca++] fluxes. These signals regulate actin binding proteins to locally modulate actin polymerization, interactions and force transduction to steer the growth cone leading margin towards the sources of attractive cues and away from repellent guidance cues.

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

“…Many studies in several model organisms, including C. elegans, indicate that axon growth and guidance are ultimately regulated by actin cytoskeleton remodeling at growth cones (Kalil and Dent, 2005;Quinn and Wadsworth, 2008;Dent et al, 2011;Chia et al, 2014;Gomez and Letourneau, 2014). We therefore postulated that JMJD-1.2 might regulate actin dynamics and tested this by systematically ablating several conserved actin regulators in the jmjd-1.2 genetic background and further analyzing the axon migration of PVQ neurons.…”

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

“…The complex signaling network initiated by guidance cues ultimately regulates, at growth cones, the dynamics of filopodia and lamellipodia, actin-based structures required for axon growth, branching and guidance (Kalil and Dent, 2005;Dent et al, 2011;Chia et al, 2014;Gomez and Letourneau, 2014). The role of WASP, WAVE and Ena/VASP in regulating axon growth and guidance by controlling filopodia formation (Drees and Gertler, 2008;Bear and Gertler, 2009;Tahirovic et al, 2010) is evolutionarily conserved and their C. elegans homologs (WSP-1, WVE-1 and UNC-34) are described as the main downstream targets of the signaling pathways regulating axon migration ( Fig.…”

“…Indeed, evolutionarily conserved molecules regulating actin dynamics, such as WSP-1/WASP (WAS), UNC-34/Ena/VASP and WVE-1/WAVE (WASF1), have been shown to contribute to correct axon guidance by integrating multiple signaling pathways (Luo, 2002;Koleske, 2003;Norris et al, 2009;Dent et al, 2011;Mohamed et al, 2012;Chia et al, 2014;Gomez and Letourneau, 2014). The WASP and WAVE protein families, which ensure maximal actin nucleation through the activation of the Arp2/3 complex (Takenawa and Suetsugu, 2007;Pollitt and Insall, 2009), act in response to Netrin and Semaphorins (Zallen et al, 2002;Shekarabi et al, 2005).…”

Mathematical-Computational Simulation of Cytoskeletal Dynamics

“…2.2) [14,23]. Growth cones are the motile tips of growing axons, the long and slender processes of nerve cells which form the cables that wire the nervous system.…”

“…To lay these cables during development or regeneration, the growth cones at their tips navigate along specified paths, and their prominent filopodia act as sensors facilitating proper navigation [55]. Apart from the fact that growth cones display prominent filopodia with a clearly defined function, there is a good conceptual understanding of the fundamental roles that actin plays in growth cones, and their actin machinery is well investigated in this context [23,41].…”