Figure 1.

Sequence of cytoskeletal events leading to the formation of axon collateral branches. The schematic shows the formation of a collateral branch, in time (left to right), along an axon (A). The first event in the formation of a branch is the emergence of an axonal filopodium (B–C). The emergence of an axonal filopodium is preceded by the formation of an axonal actin filament patch (B). The actin patch is a meshwork of actin filaments that gives rise to the bundle of actin filaments that defines the core of the filopodium (C). The targeting of an axonal microtubule into the filopodium is the next necessary step in the formation of a branch from a filopodium (D). The inset shows the general distributions of Drebrin and Septin 7 at axonal filopodia. Septin 7 localizes specifically to the base of filopodia and Drebrin localizes to actin patches and the proximal half of filopodia. Note that although not specifically shown, actin patches have shorter lifespans than filopodia and often are not present at the base of existing filopodia, although remnants may persist. Filopodia containing microtubules that remain in place have the potential to mature into nascent branches. The process of maturation involves the disassembly of the filopodial actin filament bundle, and the establishment of a distally polarized actin filament cytoskeleton giving rise a small growth cone-like structure at the tip of the nascent branch (E). Once the branch if established it then has the potential to continue elongating or undergo retraction back into the main axon. Each of the steps B–E has a given probability of occurring. In other words, only subsets of actin patches give rise to filopodia, only subsets of filopodia are targeted by microtubules, and only a subset of filopodia containing microtubules undergo maturation. Ultimately a branch arises from a segment of the axon that has successfully met the criteria for each of these steps. Not shown in this schematic is the local splaying of the microtubule array at sites of potential branching that is however discussed in the main text. The splaying occurs early in the process between steps A–B. (F) Summary of molecules discussed in the main text with specific identified roles in steps A–E. Each set of regulators is shown below the relevant step. Other regulators of branching which have not been assigned specific loci of regulation in the cytoskeletal basis of branching are not shown, but discussed in the text. Under (B) regulators are shown depending on whether they control the initiation of patches or their subsequent development (i.e., increase in size and lifespan). Unless denoted by (−) the role of the regulator is positive. If denoted by (−) the role is inhibitory. For example, Myosin II acts to suppress the emergence of filopodia from actin patches (C). In (B) Drebrin is denoted with a (*) to note that while it is required for patch initiation it is not sufficient to drive initiation. In (E) myosin II is denoted with (*). In this case, Myosin II does not regulate the entry of microtubules into filopodia but it serves to decrease the distance the microtubules penetrate into the filopodium.