Inhibiting Clarinet/CLA-1 restores function to injured motor neurons

To regain function, injured axons need to both regenerate and reform synapses with appropriate postsynaptic cells. We found that inhibiting the scaffolding protein Clarinet/CLA-1, a C. elegans ortholog of Piccolo and Fife, robustly improves axon regeneration. Despite the importance of CLA-1 during synapse development, disrupting the medium isoform of CLA-1 increases the number of axons that regenerate to the neuromuscular junction without significantly influencing synapse reformation. Consequently, the axons that do regenerate are capable of regaining function. Mechanistically, the enhanced axon regeneration observed in cla-1(-) mutants depends on the function of PTRN-1, a microtubule minus-end binding protein. Our data supports a model where loss of CLA-1 promotes PTRN-1 function, which speeds trafficking of injury-related cargo to and from the lesion, thus improving repair. Together, our results reveal a highly conserved synaptic active zone protein that can be manipulated to enhance axon regeneration without sacrificing the function of the repaired axons. HighlightsO_LIClarinet/CLA-1 is a robust inhibitor of C. elegans GABAergic axon regeneration C_LIO_LILoss of CLA-1 function improves both axon regeneration and functional repair C_LIO_LICLA-1 isoforms differentially regulate axon regeneration and synaptic transmission C_LIO_LICLA-1 regulates axon regeneration via microtubule minus-end protein PTRN-1/Patronin C_LIO_LICLA-1 knockdown improves cargo trafficking during the early injury response C_LI