| Autor: |
Cadiz Diaz A; Department of Biology, University of Miami, Coral Gables, FL 33146., Schmidt NA; Department of Biology, University of Miami, Coral Gables, FL 33146., Yamazaki M; Department of Regenerative Biology and Medicine, MDI Biological Laboratory, Bar Harbor, ME 04672., Hsieh CJ; Department of Biology, University of Miami, Coral Gables, FL 33146., Lisse TS; Department of Biology, University of Miami, Coral Gables, FL 33146.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, FL 33136., Rieger S; Department of Biology, University of Miami, Coral Gables, FL 33146.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, FL 33136. |
| Abstrakt: |
Tissue wounding induces cutaneous sensory axon regeneration via hydrogen peroxide (H 2 O 2 ) that is produced by the epithelial NADPH oxidase, Duox1. Sciatic nerve injury instead induces axon regeneration through neuronal uptake of the NADPH oxidase, Nox2, from macrophages. We therefore reasoned that the tissue environment in which axons are damaged stimulates distinct regenerative mechanisms. Here, we show that cutaneous axon regeneration induced by tissue wounding depends on both neuronal and keratinocyte-specific mechanisms involving H 2 O 2 signaling. Genetic depletion of H 2 O 2 in sensory neurons abolishes axon regeneration, whereas keratinocyte-specific H 2 O 2 depletion promotes axonal repulsion, a phenotype mirrored in duox1 mutants. Intriguingly, cyba mutants, deficient in the essential Nox subunit, p22Phox, retain limited axon regenerative capacity but display delayed Wallerian degeneration and axonal fusion, observed so far only in invertebrates. We further show that keratinocyte-specific oxidation of the epidermal growth factor receptor (EGFR) at a conserved cysteine thiol (C797) serves as an attractive cue for regenerating axons, leading to EGFR-dependent localized epidermal matrix remodeling via the matrix-metalloproteinase, MMP-13. Therefore, wound-induced cutaneous axon de- and regeneration depend on the coordinated functions of NADPH oxidases mediating distinct processes following injury. |
