Calpain activation by Wingless-type murine mammary tumor virus integration site family, member 5A (Wnt5a) promotes axonal growth.

Axon development involves spatial-temporal cytoskeletal reorganization. However, how the cytoskeleton remodeling is modulated by extracellular cues is unclear. Here, we report a role of Wnt/Ca(2+) signaling in regulating actin and growth cone dynamics. We found that treatment of cultured cortical neurons with Wnt5a, a non-canonical Wnt, either globally or locally, caused an increase in the activity of calpain, a calcium-dependent protease responsible for the cleavage of several actin binding proteins, including spectrin. Treatment with Wnt5a promoted growth cone advance, as well as axonal growth, and these effects were prevented by chelating intracellular calcium, inhibition or down-regulation of calpain, or blockade of spectrin cleavage by competitive peptides. Interestingly, both Wnt5a and activated calpain were found to be mainly distributed in the axon-rich intermediate zone of neocortex. Down-regulating calpain expression interfered with the growth of callosal axons in vivo. Thus, Wnt5a serves as a physiological cue to stimulate localized calpain activity, which in turn promotes growth cone advance and axonal growth.