TIR-1/SARM1 Inhibits Axon Regeneration

An injured axon has two choices, regenerate or degenerate. In many neurons, the result is catastrophic axon degeneration and a failure to regenerate. To coerce the injured nervous system to regenerate, the molecular mechanisms that regulate both axon regeneration and degeneration need to be defined. We found that TIR-1/SARM1, a key regulator of axon degeneration, inhibits regeneration of injured motor axons. Loss of tir-1 function both reduces the frequency with which severed axon fragments degenerate and increases the frequency of axon regeneration. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration. Rather, TIR-1 carries out each of these opposing functions cell autonomously by regulating independent downstream genetic pathways. While promoting axon degeneration with the DLK-1 mitogen activated protein kinase (MAPK) signaling cascade, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade. Our finding that TIR-1 regulates both axon regeneration and degeneration provides critical insight into how axons coordinately regulate the two key responses to injury, consequently informing approaches to manipulate the balance between these responses towards repair.