An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis

Injured axons synthesize the RNA Binding Protein KHSRP that promotes mRNA decay and slows nerve regeneration. Axotomy-induced increase in axoplasmic Ca ²⁺ activates axonal Khsrp translation, and while Ca ²⁺ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of Reg3a and Khsrp sustains axonal KHSRP levels in regenerating axons. Nerve injury activates Reg3a expression, resulting in increased REG3A synthesis and secretion from axons. REG3A stimulates ER Ca ²⁺ release to activate PERK, increase eIF2 α phosphorylation, and increase Khsrp translation. Axoplasmic Ca ²⁺ slowly oscillates in growth cones and Reg3A depletion attenuates growth cone Ca ²⁺ oscillations, decreases KHSRP synthesis, reduces the axon's retractive events, and accelerates peripheral nerve regeneration. Thus, REG3A to KHSRP signaling provides an axon-intrinsic loop that decelerates axon growth through localized mRNA translation.