Introduction The cytoskeleton allows cells to

Introduction The cytoskeleton allows cells to establish, maintain and transform their shape. In neurons, these include cell differentiation, migration, polarization and development of their unique arborization. Axons are very thin (~1 μm), long (up to 1m) and highly branched (>95% of the plasma membrane of a typical neuron) extensions, presenting unique challenges to the cytoskeletal organization (Kevenaar and Hoogenraad, 2015; Leterrier et al., 2017). The axonal architecture must be reliably maintained for decades, but also adapt for optimal functioning in a range of physiological conditions (Jamann et al., 2018). On the one hand, the organization of axonal microtubules and their associated proteins have been extensively studied, although numerous questions remain (Kapitein and Hoogenraad, 2015; Prokop, 2013). On the other hand, MK-0457 is well known to support morphogenesis via the dynamic formation of structures such as lamellipodia, filopodia and stress fibers (Blanchoin et al., 2014). Axonal actin has indeed been recognized as a component of dynamic structures in developing axons such as the growth cone and nascent branches, with a less-studied role of structural support in mature axons (Gallo, 2013; Letourneau, 2009). However, this vision has been profoundly transformed by the discovery of new actin structures within axons such as rings, hotspots and trails (Leterrier et al., 2017; Roy, 2016). Most of our knowledge about axonal actin comes from dissociated neuronal cultures; these reductionist models have been invaluable for isolating the core cell-intrinsic processes described here, and a number of them – such as actin rings, hotspots and trails – have been since described in more integrated models. This review aims at summarizing the current knowledge about axonal actin, with a particular focus on the compartments of mature axons: the axon initial segment, axon shaft and presynaptic boutons. We will concentrate on structural aspects, detailing the different actin assemblies and their established or putative role, leaving mostly aside the myriad of molecular pathways and binding partners that affect actin assembly in various axonal compartments (for reviews see Coles and Bradke, 2015; Menon and Gupton, 2016).
Dynamic actin during axon development The striking arrangement of enriched actin in structures such as the growth cone has captured the interest of many neuroscientists, from early electron and fluorescence microscopy work (Kuczmarski and Rosenbaum, 1979; Letourneau, 1983; Yamada et al., 1971) to the first live-cell imaging studies (Lin and Forscher, 1995; O'Connor and Bentley, 1993). The intrinsic dynamics of actin polymers, with biased incorporation of actin monomers at the barbed end and disassembly at the pointed end, naturally suggested a role for force generation, morphogenesis and cellular movement (Kirschner, 1980; Wessells et al., 1971). Actin is indeed crucial during axonal development: sprouting of the first neurites and subsequent axonal specification, elongation and branching are driven by dynamic actin-driven processes (Letourneau, 2009). We will only briefly describe these processes, and invite the interested reader to consult more comprehensive reviews on this subject (Caceres et al., 2012; Omotade et al., 2017; Schelski and Bradke, 2017; Witte and Bradke, 2008) (Fig. 1).
Actin assemblies in the mature axon By contrast with the dynamic assemblies in developing neurons, actin labeling along the axon shaft itself was initially considered as weak and unremarkable (Letourneau, 2009). Fluorescent labeling showed a uniform distribution of actin with occasional clusters (Kuczmarski and Rosenbaum, 1979; Letourneau, 1983; Spooner and Holladay, 1981), and electron microscopy could resolve a homogeneous submembrane population (Hirokawa, 1982; Tsukita et al., 1986) as well as more intra-axonal short filaments (Bearer and Reese, 1999; Fath and Lasek, 1988). In recent years however, super-resolution microscopy and live-cell imaging have profoundly transformed this view, with the discovery of striking structures along the axon shaft such as the exquisitely organized actin rings or the dynamic hotspots and trails (Leterrier et al., 2017) (Fig. 2).