What it is
Injured axons make the RNA-binding protein KHSRP, which promotes mRNA decay and slows nerve regeneration. A rise in axoplasmic calcium triggers KHSRP translation after axotomy, and although calcium returns to pre-injury levels within 16 hours, axonal KHSRP stays elevated because the alternating translation of two transcripts, Reg3a and Khsrp, sustains it. Secreted REG3A stimulates ER calcium release that activates PERK, raises eIF2 alpha phosphorylation, and drives further Khsrp translation. Depleting Reg3a attenuates growth-cone calcium oscillations, lowers KHSRP synthesis, reduces the axon's retractive events, and accelerates peripheral nerve regeneration.
Why it matters
Peripheral axons regrow slowly, and the axon-intrinsic controls that restrain their own regeneration have been poorly defined. This work identifies a self-sustaining REG3A-to-KHSRP loop, built from proteins synthesized locally in the axon, that keeps decelerating growth even after the injury calcium signal subsides within 16 hours.
How to read this
Because depleting Reg3a speeds regeneration, REG3A-to-KHSRP signaling marks a defined molecular target for accelerating recovery after peripheral nerve injury.
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