Schwann cell adaptation in peripheral nerve repair

• Applicants: Professorin Dr. Juliane Bremer; Professorin Dr. Ruth Martha Stassart
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567102932

Successful nerve repair depends on tightly coordinated processes of nerve degeneration and regeneration, which critically rely on peripheral nerve glial cells, the Schwann cells. After injury, Schwann cells align into long cellular cords known as Büngner Bands, which are essential for guiding regenerating axons back to their original targets. However, the molecular mechanisms governing this process remain largely unknown. The formation of Büngner Bands involves a striking morphological conversion of Schwann cells, characterized by substantial elongation and the extension of overlapping cellular processes. In our preliminary studies, we observed a strong induction of cytoskeletal regulators following nerve injury. Using an in vitro assay designed to screen for dynamic Schwann cell interactions, we identified several key genes involved in actin cytoskeleton remodeling, particularly those associated with the WASP (Wiskott-Aldrich Syndrome Protein) family and the WAVE regulatory complex (WRC). Notably, while Schwann cells form the Büngner Bands, they, at the very same time, also need to break down large amounts of myelin debris, and we recently discovered Schwann cells to respond to acute nerve injury with a profound metabolic and mitochondrial adaptation. We here hypothesize that cytoskeletal and mitochondrial dynamics are interdependent and mechanistically linked in repair Schwann cells, and that both processes are essential for Büngner Band formation after nerve injury. To test this hypothesis, we will use two complementary model systems - zebrafish and mice - to first (AIM 1) characterize Schwann cell remodeling, F-actin dynamics, and mitochondrial adaptations during Büngner Band formation using state-of-the-art live imaging and 3D electron microscopy. Based on this framework, we will then (AIM 2) investigate the role of cytoskeleton-mitochondria interactions for Büngner Schwann cells and nerve regeneration by pharmacologically and genetically targeting actin cytoskeletal regulators and mitochondrial dynamics in vivo, based on candidate genes identified in our preliminary data. Our research aims to advance our understanding of the cellular, molecular, and metabolic mechanisms that Schwann cells employ to promote peripheral nerve repair following acute trauma.

• DFG Programme: Research Grants