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.