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

Abstract

Injured axons synthesize the RNA Binding Protein KHSRP that promotes mRNA decay and slows nerve regeneration. Axotomy-induced increase in axoplasmic Ca²⁺ activates axonal <i>Khsrp</i> translation, and while axonal Ca²⁺ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of <i>Reg3a</i> and <i>Khsrp</i> sustains KHSRP levels in regenerating axons. Axonal <i>Reg3a</i> 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 <i>Khsrp</i> translation. Axoplasmic Ca²⁺ slowly oscillates in growth cones of cultured neurons and <i>Reg3a</i> 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.