The axonal cytoskeleton: from organization to function

Abstract

The axon is the single long fiber that extends from the neuron and transmits electrical signals away from the cell body. The neuronal cytoskeleton, composed of microtubules (MTs), actin filaments and neurofilaments, is not only required for axon formation and axonal transport but also provides the structural basis for several specialized axonal structures, such as the axon initial segment (AIS) and presynaptic boutons. Emerging evidence suggest that the unique cytoskeleton organization in the axon is essential for its structure and integrity. In addition, the increasing number of neurodevelopmental and neurodegenerative diseases linked to defect in actin- and microtubule-dependent processes emphasizes the importance of a properly regulated cytoskeleton for normal axonal functioning. Here, we provide an overview of the current understanding of actin and microtubule organization within the axon and discuss models for the functional role of the cytoskeleton at specialized axonal structures.

Keywords: actin; axon; axon initial segment; cytoskeleton; kinesin; microtubule; presynapse; transport.

Figure 1

The axonal cytoskeleton and axon-specific structures. The axon is specialized in transmitting information to other cells. To ensure this function, the axon has a unique cytoskeletal organization (A,B) and has several specialized structures (C,D). (A) The unique unipolar orientation of the microtubules (MTs) within the axon provides anterograde transports of various axonal cargoes via plus-end directed kinesins. Various mechanisms exist that regulate the activity of kinesins. (B) The actin cytoskeleton within the axon exists as periodically spaced rings underneath the axonal plasma membrane, organized by spectrin and adducing, and provides the axon with elastic and stable support. Along the axon, bundles of actin are present. (C) The axon initial segment (AIS) is important for the initiation of action potentials and maintaining neuronal polarization by acting as a transport filter. Within the AIS, a dense meshwork of cytoskeletal and scaffolding proteins exists where Ankyrin-G (AnkG) links transmembrane proteins to the actin and microtubule cytoskeleton. (D) At the presynaptic site, neurotransmitter-filled synaptic vesicles (SVs) are docked at the presynaptic membrane and undergo exocytosis upon the arrival of an action potential. Within the presynapse, actin is proposed to exist in a branched network where it may function in the controlling exo- and endocytosis, recruiting and positioning of SVs and organizing the active zone (AZ).