UNRAVELING THE MOLECULAR DETERMINANTS OF AXONAL REGENERATION: A COMPARATIVE ANALYSIS OF CNS AND PNS AXONS

Axon regeneration in the mature central nervous system (CNS) is highly restricted, leading to irreversible neuronal damage and permanent deficits following injury. In contrast, mature peripheral nervous system (PNS) and developing CNS axons exhibit robust regenerative capacity, often restoring function. While these differences have primarily been attributed to extrinsic factors, recent evidence highlights a critical role for axon-intrinsic RNA-related mechanisms in supporting neuronal survival and regeneration, yet the intrinsic mechanisms limiting regeneration in mature CNS axons remain unclear.
Here, we investigated molecular similarities and differences between developing CNS, mature CNS, and mature PNS axons to identify intrinsic determinants of regeneration competence. Using high-throughput transcriptomic and proteomic analyses, we examined early axonal responses to injury independently of microenvironmental or somatic influences. Consistent with this, each system retained a distinct basal and injury-induced molecular identity, closely aligned with its regenerative capacity. Axotomy induced extensive molecular remodeling in all axonal populations, with minimal overlap in regulated RNAs, proteins, or functional pathways.
We further identified RNA-binding proteins as key intrinsic regulators of these divergent states and uncovered a battery of differentially expressed molecules involved in multiple aspects of axonal RNA metabolism. Among these, we identified a splicing-associated RNA-binding protein selectively retained in regeneration-competent axons, whose gain-of-function permissively enhanced intrinsic axon growth in a regeneration-limited CNS context.
Together, these findings identify axon-intrinsic molecular state and resource allocation as critical determinants of regeneration and help explain the limited regenerative capacity of adult CNS axons.