Numerous axon guidance molecules including Semaphorins, Ephrins, Wnts, Slits, and Netrins become upregulated

in the adult CNS after injury (Giger et al., 2010). These factors have received much attention in regenerative studies because they are candidates for modulating the growth of axons in adults. Blocking EphA4-signaling with an infused MAPK Inhibitor Library manufacturer peptide antagonist enhances sprouting of corticospinal axons rostral to the injury site but is insufficient to promote axonal regeneration across the lesion (Fabes et al., 2007). Likewise, inhibiting receptor binding of Sema-3A by a small compound (SM-216289) accelerates axon olfactory nerve regeneration and promotes serotonergic axon growth after spinal cord injury but fails to enhance corticospinal or ascending

sensory axon growth (Kaneko et al., 2006 and Kikuchi et al., 2003). This is consistent with the finding that mice deficient in the receptors for class 3 semaphorins, Plexin-A3 and Plexin-A4, fail to regenerate serotinergic or corticospinal axons after a transection (Lee et al., 2010). Thus, efforts to modulate known axon guidance signaling pathways to promote axonal regeneration have met with limited success to date but remain a promising avenue to explore for complementing other methods to promote regeneration. In principle, targeting receptor proteolysis might provide a novel route for modulating intrinsic axonal responsiveness of adult CNS Volasertib manufacturer neurons (Figure 1B). The lessons learned from developmental studies of guidance receptor proteolysis suggest this strategy might be useful for (1) broadly reducing the sensitivity of inhibitory receptors, (2) increasing the sensitivity of growth promoting/attractive receptors, or even

(3) switching axonal responsiveness to environmental guidance molecules from repulsion to attraction. These effects could be achieved using specific protease inhibitors or overexpression of receptor fragments like DCC stubs with potent attractive signaling activity. The development, maintenance, and repair Non-specific serine/threonine protein kinase of the nervous system are delicately balanced between progressive and regressive events. Neural wiring, axon attraction, and local protein translation can be offset by neurodegeneration, axon repulsion, and proteolysis. These Ying and Yang events are interdependent, interconnected, and transformable (Figure 1A). Increasingly, axon guidance receptor signaling has gained attention in the context of development, degeneration, and regeneration (Figure 1B and Table 2). Here, we reviewed recent progress in our understanding of axon guidance factor proteolysis and the role that cleavage plays in transforming the activity of these important signaling proteins.