The growth cone of migrating neurons as a primary sensor and migratory actuator in the injured brain environment

Axonal growth cones mediate axonal guidance and growth regulation and their activities are crucial for neuronal circuit development. However, the function of growth-cone-like structure at the tip of leading process of migrating neurons is largely unknown. Here, using live imaging analyses, we show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate proteoglycans (CSPG), extracellular matrix molecule upregulated in the injured brain, through PTPσ and collapse, which leads to inhibition of neuronal migration. In the CS-enriched inhibitory environment, the growth cone can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), which induces tyrosine phosphorylation of Cortactin, thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration (Nakajima et al., Nat. Com. 2024). This study provides a strong rationale for promoting neuronal migration through growth cone regulation to remedy brain injury.