Mitf is a Schwann Cell Sensor of Axonal Integrity that Drives Nerve Repair

Abstract

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. Taken together, our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf, which is critical for activating cellular plasticity and counteracting neural disease.

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration

“…Neuregulin-1 type III (NRG1) is located on the axonal surface where it interacts with the epithelial growth factor receptor (EGFR) family members ErbB2 and ErbB3 produced by SC (Zhao et al 2022). NRG1 regulates SC differentiation and is important for induction and maintenance of the myelinating state (Quintes et al 2010; Daboussi et al 2023). Because the SC repair program is not effectively activated in Sarm1-/- nerves ex vivo , this provided an opportunity for pharmacological examination of signaling pathways that suppress induction of the repair program.…”