Mitf is a Schwann cell sensor of axonal integrity that drives nerve repair

• Published in: Cell reports (Cambridge) 2023-11, Vol.42 (11), p.113282-113282, Article 113282
• Main Authors: Daboussi, Lydia, Costaguta, Giancarlo, Gullo, Miriam, Jasinski, Nicole, Pessino, Veronica, O’Leary, Brendan, Lettieri, Karen, Driscoll, Shawn, Pfaff, Samuel L.
• Format: Article
• Language: English
• Subjects: Axons - metabolism; Cell Plasticity; CP: Neuroscience; Humans; injury; Mitf; Nerve Regeneration - physiology; neurodegeneration; peripheral nerve; Peripheral Nerve Injuries - genetics; Peripheral Nerve Injuries - metabolism; Peripheral Nervous System Diseases - metabolism; phosphoinositide; regeneration; Schwann cell; Schwann Cells - metabolism; Sciatic Nerve - metabolism; Signal Transduction - physiology; transdifferentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113282

Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined, and consequently, it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here, we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism, and dedifferentiation are misexpressed, and nerve repair is disrupted. Our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf nuclear localization, which is critical for activating cellular plasticity and counteracting neural disease. [Display omitted] •Mitf-induced Schwann cell plasticity is triggered by peripheral neuropathy•Nrg-ErbB signaling activates Mitf via cytoplasmic-to-nuclear translocation•Mitf restores sensorimotor function following axonal breakdown•Mitf regulates a core repair program across injury and neurodegeneration Daboussi et al. identified Mitf as a Schwann cell-autonomous sensor that detects axonal damage from injury and disease via Nrg-Erbb-PI3K-mTorc2 signaling. Activation of MITF induces nuclear translocation and induction of repair. These data demonstrate that the pathways controlling cellular plasticity are an important entry point for attenuating PNS neurodegeneration.