Coordination of the axonal cytoskeleton during the emergence of axon collateral branches.

Abstract

The formation of branches during development allows a single axon to make synaptic contacts with numerous target neurons, often in different parts of the nervous system, thereby allowing for the establishment of complex patterns of neuronal connectivity. Following injury, the formation of collateral branches contributes to the endogenous neuroplasticity which depending on the neuronal population can have beneficial (e.g., formation of compensatory relay circuitry) or adverse effects (e.g., development of autonomic dysreflexia). The formation of axon collateral branches from the axon shaft involves a complex series of signaling events and cytoskeletal reorganization. The initial step in the formation of a collateral branch is the emergence of axonal filopodia, supported by a bundle of actin filaments (Figure 1A). However, axonal filopodia are generated from precursor structures consisting of small meshworks of actin filaments, termed actin patches (Figure 1A inset). Actin patches are dynamic structures which form along the axon shaft, grow in size and subsequently are disassembled (for reviews on actin patches see Gallo, 2011, 2013). Although in live imaging studies using fluorescently labeled actin most axonal filopodia arise from a detectable actin patch, only a subset of patches gives rise to filopodia before dissipating. As the duration of filopodia is longer than that of patches, they are often not detected at the base of longer pre-existing filopodia, although they often re-emerge at the base of existing filopodia. In order for an axonal filopodium to mature into a collateral branch it must first become invaded by axonal microtubules (Figure 1A). Following the targeting and retention of axonal microtubules into the filopodium, the filopodium then begins to reorganize its actin filament cytoskeleton transitioning from a linear bundle of actin filaments to a distal accumulation of filaments giving rise to a nascent branch (Figure 1A), ultimately giving rise to a small growth cone structure at the tip of the branch. The transformation of a filopodium into a nascent branch is referred to as maturation of the branch which then grows in length (Figure 1A).