Building the elaborate neural networks required for brain function involves profound cytoskeleton remodelling during axonal growth and pathfinding. In particular, axonal growth is supported by the growth cone, a dynamic F-actin based structure, and regulated by ADF/Cofilin, an F-actin destabilising protein. Cofilin is activated by dephosphorylation by Slingshot (Ssh), and inhibited by LIMK-mediated phosphorylation. Activity of these regulators is in turn influenced by the small GTPase Rac, which acts via Pak to promote LIMK activity and inhibit Cofilin, but also via a Pak-independent, non-canonical pathway to promote Cofilin activity. However, the molecular mediators of the non-canonical pathway are currently unknown. Here (p. ), Takashi Abe and colleagues identify Sickie, a protein that can interact with both the actin and microtubule cytoskeletons, as a regulator of axonal growth in the Drosophila mushroom body. By visualizing Cofilin phosphorylation and F-actin state in vivo, the authors show that Sickie participates in the non-canonical pathway, regulating Cofilin-mediated axonal growth in a Ssh-dependent manner. This study reveals an important new regulator of Cofilin and may provide insights into the molecular basis of the coordination between actin and microtubules during axonal growth.
