Intertwined Autophagy and Integrin Dynamics Shape Axon Growth and Regeneration

Abstract

Autophagy is a central pathway for cellular homeostasis, mediating degradation and recycling of cytoplasmic components through lysosomal processing. Although autophagy has been implicated in axon growth and neuronal injury responses, its role in axon regeneration remains incompletely understood. In parallel, integrin trafficking and focal adhesion dynamics are critical determinants of axonal growth, and increasing evidence indicates that autophagy regulates focal adhesion turnover in non-neuronal cells; however, whether this mechanism operates in neurons remains unknown. Here, we investigated the dynamics of autophagy during axon growth and regeneration in adult sensory neurons and examined its relationship with integrin trafficking. Using live imaging, we analyzed autophagic vesicles and integrin-containing compartments in axons under basal conditions and following axotomy. We find that axonal injury induces marked short- and long-term alterations in distal axon and growth cone autophagic vesicle dynamics, integrin trafficking, and autophagy-associated integrin turnover. Importantly, these changes correlate with axonal growth and regenerative capacity. Furthermore, we identify a functional interplay between autophagy and integrins, suggesting bidirectional regulation in which autophagy contributes to adhesion receptor recycling, while integrins feedback to modulate autophagy. Finally, pharmacological modulation indicates that autophagy plays a critical role in both axonal growth and regeneration, and that rapamycin enhances regenerative responses, likely through modulation of autophagy-dependent integrin recycling rather than a general increase in autophagic activity. Together, these findings reveal a bidirectional feedback system between integrin-mediated extracellular cues and autophagy-dependent intracellular trafficking that jointly orchestrates axon growth and regeneration.