The Reelin‐L1CAM Signalling Axis: Orchestrating Molecular Synergy in Neural Repair and Regeneration

The roles of Reelin and L1 cell adhesion molecule (L1CAM)-long regarded as separate regulators of neuronal migration and axon guidance-are now understood as components of a complementary signal transduction axis with significant implications for neural repair. Recent evidence has shown that Reelin activates Dab1 through the receptors ApoER2 and VLDLR, inducing Src family kinase cascades and subsequent PI3K-Akt, MAPK/ERK and cytoskeletal remodelling pathways, as well as regulating the activity of L1CAM. Particularly, Reelin seems to play a role in the neurite outgrowth promoted by L1CAM through its proteolytic cleavage, its modulation of integrin activity and the coordination of kinase binding in the axonal extension process. These meticulously synchronised processes imply that there is a common input to axonal sprouting and rearrangement of synapses as well as inflammatory regulation during the posttraumatic period of central nervous system injury. Overall, Reelin and L1CAM form a mechanistically coherent network that facilitates regeneration-related signalling, thus providing a more viable basis for new therapeutic approaches that involve the use of recombinant proteins, peptides, protease regulation or gene-directed interventions to promote neural repair.