Sprouting of axon branches from the axonal shaft involves the formation of F-actin-based filopodia that are invaded by microtubules. Spiliotis and colleagues show that septins, proteins known to interact with both actin and microtubules, coordinate these two networks to achieve such collateral axonal branching (Curr. Biol. 22, 1109–1115; 2012).

Septins 6 and 7 (SEPT6 and SEPT7) were previously implicated in dendritic morphogenesis. By manipulating SEPT6 and SEPT7 levels in chick embryo dorsal root ganglia neurons, the authors established that they are both required for collateral axon branching. However, further analyses demonstrated that SEPT6 and SEPT7 have distinct axonal localizations and functions. SEPT6 accumulates at axonal F-actin patches, the regions of filopodia and axonal branching initiation, where it regulates filopodia formation by increasing the recruitment of cortactin, an activator of Arp2/3-dependent actin polymerization. In contrast, SEPT7 alters the organization of the axonal cytoskeleton to mediate the entry of microtubules into filopodia. Although the precise mechanisms through which SEPT6 and SEPT7 achieve these effects remain to be elucidated, these findings highlight septins as cytoskeletal regulators that are able modulate both the actin and microtubule cytoskeletons for formation of collateral axon branches.