Salk researchers report they have discovered a protein called Mitf that mediates the repair function in the peripheral nervous systems of mice. The protein Mitf helps turn on the repair function of specialized nervous system Schwann cells. These findings have the potential to lead to novel therapeutics that bolster repair function and heal peripheral neuropathy.

Their new study is published in Cell Reports in an article titled, “Mitf is a Schwann cell sensor of axonal integrity that drives nerve repair.”

“Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function,” the researchers wrote. “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.”

“We wanted to know what mechanisms control damage response in peripheral nerves under varying conditions—like acute trauma, genetic disorders, or degenerative diseases,” said Samuel Pfaff, PhD, senior author, professor, and Benjamin H. Lewis chair at Salk. “We found that Schwann cells, which are special cells in nerves that protect and support neurons’ axons, enter their repair state because of a pathway mediated by the protein Mitf.”

Pfaff and his team focused on understanding neurons and Schwann cells, which protect healthy neurons and repair damaged ones.

The peripheral nervous system’s ability to repair damage is remarkable. Yet, the mechanisms that orchestrate this process have remained poorly understood.

To unravel how Schwann cells differentiate to begin repairing peripheral nerve damage, the researchers looked at mouse models of Charcot Marie Tooth disease (CMT), a type of hereditary neuropathy.

“Going into this project, I thought that when you have a genetic nerve degeneration disorder, cells are dying and recovery isn’t possible,” explained first author Lydia Daboussi, PhD, a former postdoctoral researcher in Pfaff’s lab and current assistant professor at the University of California, Los Angeles. “But our findings show that there are gene programs turned on by Mitf that repair some of the damage done in those chronic disease scenarios, and when you turn those programs off, disease symptoms get worse.”

In mice with CMT, the researchers noticed that the Schwann cells completing the repairs had high levels of Mitf in their nuclei—where the genetic instructions for how to be a Schwann cell and how to conduct repairs are stored.

Upon investigation of this relationship between Mitf and Schwann cells, they found that Mitf was in the cytoplasm of Schwann cells until sensing neuronal damage. Damage then prompted Mitf to relocate from the cytoplasm of the cell to the nucleus, where it would direct the Schwann cell to make repairs.

To validate the importance of Mitf in creating repair Schwann cells, the researchers removed Mitf altogether. In both trauma and CMT, nerve repair was arrested in the absence of Mitf—demonstrating that Mitf is required for peripheral nerve repair and regeneration.

According to Daboussi, Mitf acts like a fire extinguisher. Always there, sitting in the Schwann cell, unnoticed until damage occurs. And when that damage occurs, Mitf is ready to go and immediately turns on the cell’s repair functions.

“Harnessing Schwann cell repair programs has great potential in treating chronic diseases,” added Pfaff. “It’s possible that with targeted therapeutics, we can prompt more Schwann cells to repair peripheral nerve damage and push those repairs to completion in chronic cases. Furthermore, now that we have a better grasp on the repair mechanisms, we can see if it’s possible to initiate repairs in the brain stem and spinal cord, too.”

In the future, the researchers want to look more specifically at diabetes neuropathy—the most common peripheral neuropathy condition. They also hope to explore therapeutics that bolster this repair pathway to create more Schwann cells programmed to repair damage, regardless of whether the source is trauma, genetics, or development over time.

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