PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition

Abstract

Axonal growth from both intact and severed fibers is limited after adult mammalian CNS injury. Myelin proteins contribute to inhibition of axonal growth. Semaphorin6A protein inhibits the extension of developing axons and is highly expressed in adult oligodendrocytes. This expression pattern suggests that a developmental axon guidance cue contributes to the restriction of adult CNS growth. Here, we assessed the role of a Sema6A receptor, PlexinA2, in recovery from adult trauma. Adult sensory neuron inhibition by Sema6A requires PlexinA2, with complete protection in PlexinA2-/- cultures. Mice lacking another myelin inhibitor receptor, NgR1, are known to exhibit greater axonal sprouting and functional recovery after lesions of the corticospinal tract at the medullary pyramid, so we investigated PlexinA2 in this lesion. Without injury, the corticofugal projection into the cervical spinal cord is normal in adult PlexinA2 null mice. After unilateral pyramidotomy, unlesioned PlexinA2-/- corticospinal fibers sprout across the midline to innervate the contralateral gray matter of the spinal cord to a significantly greater extent than do fibers in wild type mice. Sprouted fibers display frequent synaptophysin-positive synaptic puncta. The increased axonal growth in PlexinA2-/- mice after injury is accompanied by improved behavioral recovery in a pellet retrieval task using the impaired forelimb, and in a tape removal task. Thus, PlexinA2, as a receptor for oligodendrocyte-derived Sema6A and for secreted class 3 Semaphorins, plays a role in limiting adult axon growth and recovery after trauma.

Towards an understanding of semaphorin signalling in the spinal cord

“…As such, Sema6A to PlxnA4 signalling is most likely responsible for the correct decussation of corticospinal tract axons. Interestingly, PlxnA2 expressing corticospinal tract axons are repelled by Sema6A located on oligodendrocytes aggregated at the pyramidotomy injury site, which is significantly reduced in PlxnA2 mutants (Shim et al, 2012).…”

“…Sema6A has attracted attention due to its involvement in corticospinal tract formation (Runker et al, 2011). It is expressed in oligodendrocyte precursors during brain development, where it plays roles in their differentiation and myelinating functions (Bernard et al, 2012;Shim et al, 2012). Sema6A knock-out mice demonstrate alterations in the formation of the corticospinal tract mainly in the failure of axons to pass through the mid-hindbrain boundary into the medulla and also a failure of axons to decussate as normal in the medullary pyramids, the latter feature replicated in PlxnA4 mutants (Runker et al, 2008).…”

“…Multiple factors contribute to the failure of axonal regeneration following SCI, including neuronal death, loss of growth factors, loss of myelin, disrupted vasculature and growth inhibitory signals stemming from the glial scar, such as chondroitin sulphate proteoglycan (CSPG), MAG, nogo and semaphorins (Silver and Miller, 2004). Classes 3, 4, 6 and 7 semaphorins are all present at the glial scar (Kopp et al, 2010;Moreau-Fauvarque et al, 2003;Pasterkamp et al, 1999;Shim et al, 2012) and inhibition of class 3, 4 and 6 semaphorins has increased functional recovery in animal models (Kaneko et al, 2006;Kopp et al, 2010;Shim et al, 2012;Zhang et al, 2014). In lesions where the meningeal layer is spared astrocytes are the main component of the scar, whilst both fibroblasts and astrocytes contribute to the injury site in transection lesions, where the meningeal covering is compromised (see Fig.…”

Scar-modulating treatments for central nervous system injury

“…For example, after unilateral pyramidal transection in the medulla, PlexinA2-null mice exhibited the sprouting of unlesioned corticospinal fibers across the midline to innervate the contralateral gray matter of the spinal cord, accompanied by improved behavioral recovery [144] . However, another fi nding suggested limitations of targeting Semaphorin-mediated inhibition for promoting spinal axon regeneration, thus raising an issue of whether Semaphorin 3A modulates injury-induced axonal growth in a less severe injury model and whether receptors other than Plexins may mediate the inhibition of Semaphorin in the adult CNS [145] .…”

Sensory axon guidance with semaphorin 6A and nerve growth factor in a biomimetic choice point model

“…It has also been shown to be highly expressed in adult oligodendrocytes, establishing it as part of the inhibitory environment consequent to CNS damage (Shim et al, 2012). Similarly, Ephrin-B3 is a glial-expressed transmembrane ligand that regulates guidance in the corticospinal tract (Yokoyama et al, 2001) and mediates axon pruning (Xu and Henkemeyer, 2009), and has likewise been implicated as a myelin-based inhibitor of regeneration (Benson et al, 2005).…”