Mechanisms of Schwann Cell Development and Plasticity

SUMMARY Disorders of the peripheral nervous system, particularly those that impair motor function or alter pain sensitivity, remain major clinical challenges. Current treatments are not curative and only manage secondary symptoms. Restoration of peripheral nerve function depends on the ability of Schwann cells to undergo transdifferentiation into repair cells—a complex cellular transformation that enables axonal regrowth and remyelination. This process requires tight coordination between extracellular signaling and transcriptional reprogramming. Despite advances in identifying molecular components involved in regeneration, therapeutic development has stagnated, in part because it remains unclear how injury-activated signaling cascades directly modulate transcription factor activity to drive this reprogramming. We are addressing this gap by focusing on Mitf, a member of the MiT/Tfe transcription factor family, which we have identified as an injury-induced regulator of Schwann cell plasticity. Our preliminary data show that Mitf is rapidly activated after nerve injury and is essential for repair cell formation, axonal regeneration, and sensorimotor recovery. Yet the mechanisms that govern its activation, localization, and transcriptional output remain unknown. With newly available genetic, imaging, transcriptomic, and proteomic tools, we can now dissect how injury-derived signals transmitted through the cytoplasm influence nuclear transcriptional programs to generate effective repair cells. We hypothesize that Mitf acts as a molecular integrator, linking injury-derived signals to gene expression programs that drive Schwann cell plasticity to promote peripheral neuron regeneration after injury; and that outside of acute injury it functions as a sentinel, continuously responding to nerve stress to preserve peripheral nerve integrity across lifespan. Here we propose to use integrated molecular and genetic approaches to dissect how Mitf governs Schwann cell plasticity and nerve regeneration. In this proposal we will: 1.) Identify the Mitf- dependent networks that drive Schwann cell transdifferentiation after injury 2.) Determine how phosphorylation status regulates Mitf nuclear localization and function. 3) Define the role of Mitf in maintaining Schwann cell homeostasis. These studies will establish how Mitf integrates injury-activated signaling cascades to effect transcriptional programs in peripheral glia, providing a mechanistic framework for Schwann cell plasticity and homeostasis. Project Number: 1R01NS148365-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Lydia Daboussi | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $495,164 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BN-B (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11345050