SummaryFunctional recovery and regeneration of corticospinal tract (CST) fibers following spinal cord injury by compression or dorsal hemisection in mice was monitored after application of the enzyme-deficient Clostridium botulinum C3-protein-derived 29-amino-acid fragment C3bot . This peptide significantly improved locomotor restoration in both injury models as assessed by the open-field Basso Mouse Scale for locomotion test and Rotarod treadmill experiments. These data were supported by tracing studies showing an enhanced regenerative growth of CST fibers in treated animals as visualized by anterograde tracing. Additionally, C3bot stimulated regenerative growth of raphespinal fibers and improved serotonergic input to lumbar -motoneurons. These in vivo data were confirmed by in vitro data, showing an enhanced axon outgrowth of -motoneurons and hippocampal neurons cultivated on normal or growth-inhibitory substrates after application of C3bot . The observed effects were probably caused by a non-enzymatic downregulation of active RhoA by the C3 peptide as indicated by pull-down experiments. By contrast, C3bot 154-182 did not induce neurite outgrowth in primary cultures of dorsal root ganglion cells. In conclusion, C3bot154-182 represents a novel, promising tool to foster axonal protection and/or repair, as well as functional recovery after traumatic CNS injury.

SummaryGTPases function as intracellular, bimolecular switches by adopting different conformational states in response to binding GDP or GTP. Their activation is mediated through cell-surface receptors. Rho GTPases act on several downstream effectors involved in cellular morphogenesis, cell polarity, migration and cell division. In neurons, Rho GTPases regulate various features of dendritic and axonal outgrowth during development and regeneration mainly through their effects on the cytoskeleton. This review summarizes the main functions of Rho, Rac and Cdc42 GTPases as key regulators of morphological neuroplasticity under normal and pathological conditions.

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