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 Ca²⁺ activates axonal Khsrp translation, and while axonal Ca²⁺ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of Reg3a and Khsrp sustains KHSRP levels in regenerating axons. Axonal Reg3a mRNA and protein increase proximal to the injury site days after sciatic nerve crush. REG3A stimulates ER Ca²⁺ release in axons to activate PERK, increase eIF2α phosphorylation, and increase Khsrp translation. Axoplasmic Ca²⁺ slowly oscillates in growth cones of cultured neurons and Reg3a depletion attenuates growth cone Ca²⁺ oscillations, decreases KHSRP synthesis and reduces axonal retractive events in cultured neurons, and accelerates peripheral nerve regeneration in vivo. Thus, REG3A regulation of axonal KHSRP synthesis provides a signaling loop that decelerates axon growth through localized mRNA translation.