Injury-induced Semaphorin6C/PlexinA2 signaling drives remote neuronal apoptosis and functional impairment in the adult CNS

Axonal degeneration is a major driver of disability and disease progression in several central nervous system (CNS) disorders. After injury, neurodegeneration may extend beyond the primary lesion to anatomically and functionally connected neuronal populations, contributing to secondary damage and impaired recovery. Semaphorins are developmental axon guidance molecules that may be reactivated in the adult CNS after injury. Here, we investigated whether semaphorin 6C (Sema6C), a poorly characterized semaphorin, contributes to remote neuronal degeneration after axonal damage. We used a mouse model of hemicerebellectomy (HCb), a focal CNS injury paradigm, in which unilateral removal of the cerebellar hemisphere induces axotomy and deafferentation of precerebellar neurons, particularly those of pontine nuclei. This model enables the study of remote secondary degeneration in neuronal populations anatomically connected to the primary lesion site. To define the role of Sema6C and its receptor Plexin A2 in this process, we integrated proteomic profiling, in situ hybridization, genetic silencing, recombinant protein administration, morphological analyses, and behavioral assessments. Sema6C was selectively upregulated in pontine neurons after HCb, in association with inflammatory pathway activation and JNK-dependent apoptotic signaling. In vivo Sema6C silencing reduced JNK phosphorylation and caspase-3 activation, preserved neuronal survival, and improved functional recovery. Conversely, intracerebroventricular administration of recombinant Sema6C exacerbated remote neuronal death, worsened neurological outcomes, and amplified apoptotic and neuroinflammatory responses, including increased CD68 expression and microglial remodeling. Mechanistically, Plexin A2 was identified as a Sema6C-interacting receptor upregulated in injured pontine neurons. Plexin A2 knockdown reproduced the neuroprotective effects of Sema6C silencing both in vitro and in vivo . These findings identify Sema6C/Plexin A2 signaling as an injury-induced pathway that links axonal damage to maladaptive neuroinflammation, JNK activation, and secondary neuronal loss. Targeting this pathway may represent a promising strategy to limit remote neurodegeneration and improve recovery after CNS injury.