Ena/VASP: proteins at the tip of the nervous system

Abstract

The emergence of neurites from a symmetrical cell body is an essential feature of nervous system development. Neurites are the precursors of axons and dendrites and are tipped by growth cones, motile structures that guide elongating axons in the developing nervous system. Growth cones steer the axon along a defined path to its appropriate target in response to guidance cues. This navigation involves the dynamic extension and withdrawal of actin-filled finger-like protrusions called filopodia that continuously sample their environment. Ena/VASP proteins, a conserved family of actin-regulatory proteins, are crucial for filopodia formation and function downstream of several guidance cues. Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.

Figure 1

Organization of Ena/VASP proteins. The domains and protein interaction sites are shown in the schematic. The EVH-1 binding partners Lpd and Robo are shown; other ligands not known to function in axon outgrowth and guidance are not indicated. Phosphorylation sites shared between Mena and VASP are also indicated. The amino terminal site can be phosphorylated by either PKA or PKC. The carboxy-terminal PKG site is not conserved in EVL. Note that the invertebrate Ena/VASP proteins lack these phosphorylation sites.

Figure 2

A. Localization of Ena/VASP proteins in growth cones. Growth cones contain a meshwork of actin filaments in the lamellipodium, actin filament bundles that penetrate filopodia, bundled stable microtubules in the center, and dynamic microtubules that extend into the periphery, associating with actin filaments. Ena/VASP proteins are clustered at the tips of filopodia. B. Model for regulation of Ena/VASP activity by guidance cues. Activation of Ena/VASP proteins downstream of attractive guidance cues and/or their phosphorylation by PKA might result in the protection of actin filaments from capping protein and promote addition of actin-profilin and filament elongation. In contrast, repulsive guidance cues might inhibit Ena/VASP function, potentially through phosphorylation by PKG, leading to filament capping and retraction of filopodia. It is also possible that Ena/VASP-dependent filopodial dynamics are important to sense repulsive cues initially; subsequent inhibition/inactivation of Ena/VASP may then contribute to filopodial retraction.