Calpain Activation by Wingless-type Murine Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Promotes Axonal Growth

Abstract

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 calciumdependent 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.

Mechanisms of white matter change induced by meditation training

“…Two key components of this final pathway could be axonal transport failure and calcium influx that among other targets activate cysteine proteases such as calpains whose inhibition also confers protection of injured axons in vitro and in vivo ( Ma, 2013 ; Ma et al, 2013 ). While calpains are often associated with rapid release after axonal injury, they have also been associated with axonic growth within the axon rich intermediate zone of the cortex ( Spira et al, 2003 ; Yang et al, 2011 ). Moreover, blocking of these molecular events interferes with this growth ( Yang et al, 2011 ).…”

“…While calpains are often associated with rapid release after axonal injury, they have also been associated with axonic growth within the axon rich intermediate zone of the cortex ( Spira et al, 2003 ; Yang et al, 2011 ). Moreover, blocking of these molecular events interferes with this growth ( Yang et al, 2011 ). Spira et al (2003 , p. 311) suggest “in light of the present findings, it would be interesting to examine the role of calpain ... in events that lead to morphological restructuring of neurons in relation to plasticity such as in learning and in memory acquisition processes.” To our knowledge these critical studies have not yet been done, but as described above, calpain provides a viable possibility for white matter changes in brain state training.…”

Initiation of synapse formation by Wnt-induced MuSK endocytosis

“…Genetic mutants and knockouts have demonstrated that Wnts play a crucial role in the assembly and plasticity of central synapses (Budnik and Salinas, 2011;Ciani and Salinas, 2005;Hall et al, 2000;Lucas and Salinas, 1997;Wu et al, 2010;Yang et al, 2010). Wnts are also involved at the invertebrate neuromuscular synapse (reviewed by Davis and Ghosh, 2007;Klassen and Shen, 2007).…”

Thiazolidinediones Promote Axonal Growth through the Activation of the JNK Pathway

“…Recently, it has been shown that the ligand Wnt 5A, an activator of non-canonical Wnt pathway, could play a role in the process of axonal growth and guidance [37], [38]. Treatment with Wnt 5A increased axon outgrowth and enhances the vesicle transport to growth cones in cortical neurons [38]. In addition, we previously reported that treatment with Wnt 5A rapidly induced activation of JNK pathway [32].…”

“…Non-canonical Wnt signaling pathways mediate several cellular processes through different molecular intermediates, including Rho-GTPases, intracellular calcium levels and JNK activation [32]. Recently, it has been shown that the ligand Wnt 5A, an activator of non-canonical Wnt pathway, could play a role in the process of axonal growth and guidance [37], [38]. Treatment with Wnt 5A increased axon outgrowth and enhances the vesicle transport to growth cones in cortical neurons [38].…”