RRC ID 80950
Author Czech VL, O'Connor LC, Philippon B, Norman E, Byrne AB.
Title TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration.
Journal Elife
Abstract Growth and destruction are central components of the neuronal injury response. Injured axons that are capable of repair, including axons in the mammalian peripheral nervous system and in many invertebrate animals, often regenerate and degenerate on either side of the injury. Here we show that TIR-1/dSarm/SARM1, a key regulator of axon degeneration, also inhibits regeneration of injured motor axons. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration, nor is it determined by the NADase activity of TIR-1. Rather, we found that TIR-1 functions cell-autonomously to regulate each of the seemingly opposite processes through distinct interactions with two MAP kinase pathways. On one side of the injury, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade, while on the other side of the injury, TIR-1 simultaneously promotes axon degeneration by interacting with the DLK-1 mitogen-activated protein kinase (MAPK) signaling cascade. In parallel, we found that the ability to cell-intrinsically inhibit axon regeneration is conserved in human SARM1. Our finding that TIR-1/SARM1 regulates axon regeneration provides critical insight into how axons coordinate a multidimensional response to injury, consequently informing approaches to manipulate the response toward repair.
Volume 12
Published 2023-4-21
DOI 10.7554/eLife.80856
PII 80856
PMID 37083456
PMC PMC10121217
MeSH Animals Armadillo Domain Proteins / genetics Armadillo Domain Proteins / metabolism Axons* / metabolism Cytoskeletal Proteins / metabolism Humans MAP Kinase Signaling System Mammals / metabolism Nerve Regeneration* Neurons / metabolism
C.elegans tm3036