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

ABSTRACT

To regain function, injured axons must 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.