Inhibition of myelin regeneration by tenascin proteins and the associated matrisom

• Applicant: Professor Dr. Andreas Faissner
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407698736

• Final Report Year: 2023

Final Report Abstract

Myelin sheaths are of fundamental importance for the rapid transmission of action potentials in mammalian nervous systems. Numerous disease processes affect the myelin sheath and myelin deficits result in severe nervous system dysfunction. The repair of myelin lesions is therefore of prime importance for CNS function and homeostasis. Mature oligodendrocytes cannot repair deficient myelin, but oligodendrocyte precursor cells (OPCs) can respond to lesion, proliferate and contribute to the regeneration of myelin. The past years have shown that myelin repair is inhibited by a variety of gene products, including components of the extracellular matrix (ECM), collectively designated as matrisome. In the present project, we have considered two major glycoproteins of the matrisome of the CNS, namely tenascin-C (Tnc) and tenascin-R (Tnr), with reference to myelin regeneration. Using in vitro and in vivo assays and genetically modified mouse lines, we show here that both Tnc and Tnr regulate the development of myelin sheaths in an artificial fiber myelination assay in vitro and inhibit remyelination in ex vivo explants and in a myelin lesion model in vivo. We also demonstrate that tenascin proteins affect the migration of OPCs in vitro and provide evidence that the guanine exchange factor (GEF) Vav3 is part of the signaling pathway that mediates Tncdependent effects. Thereby, we establish the tenascin proteins as important inhibitors of myelin regeneration.

Publications

• The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions. Glia, 67(2), 376-392.
  Ulc, Annika; Zeug, Andre; Bauch, Juliane; van Leeuwen, Simon; Kuhlmann, Tanja; ffrench‐Constant, Charles; Ponimaskin, Evgeni & Faissner, Andreas
  
• Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model. Frontiers in Immunology, 11.
  Wiemann, Susanne; Reinhard, Jacqueline; Reinehr, Sabrina; Cibir, Zülal; Joachim, Stephanie C. & Faissner, Andreas
  
• Tenascin-C preserves microglia surveillance and restricts leukocyte and, more specifically, T cell infiltration of the ischemic brain. Brain, Behavior, and Immunity, 91, 639-648.
  Manrique-Castano, Daniel; Dzyubenko, Egor; Borbor, Mina; Vasileiadou, Paraskevi; Kleinschnitz, Christoph; Roll, Lars; Faissner, Andreas & Hermann, Dirk M.
  
• Brevican, Neurocan, Tenascin-C, and Tenascin-R Act as Important Regulators of the Interplay Between Perineuronal Nets, Synaptic Integrity, Inhibitory Interneurons, and Otx2. Frontiers in Cell and Developmental Biology, 10.
  Mueller-Buehl, Cornelius; Reinhard, Jacqueline; Roll, Lars; Bader, Verian; Winklhofer, Konstanze F. & Faissner, Andreas
  
• Tenascin-C restricts reactive astrogliosis in the ischemic brain. Matrix Biology, 110, 1-15.
  Dzyubenko, Egor; Manrique-Castano, Daniel; Pillath-Eilers, Matthias; Vasileiadou, Paraskevi; Reinhard, Jacqueline; Faissner, Andreas & Hermann, Dirk M.
  
• Tenascins Interfere With Remyelination in an Ex Vivo Cerebellar Explant Model of Demyelination. Frontiers in Cell and Developmental Biology, 10.
  Bauch, Juliane; Ort, Sina Vom; Ulc, Annika & Faissner, Andreas
  
• The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model. Cells, 11(11), 1773.
  Bauch, Juliane & Faissner, Andreas
  
• The guanine nucleotide exchange factor Vav3 intervenes in the migration pathway of oligodendrocyte precursor cells on tenascin-C. Frontiers in Cell and Developmental Biology, 10.
  Schäfer, Ina; Bauch, Juliane; Wegrzyn, David; Roll, Lars; van Leeuwen, Simon; Jarocki, Annika & Faissner, Andreas
  
• Regulation of the E/I-balance by the neural matrisome. Frontiers in Molecular Neuroscience, 16.
  Mueller-Buehl, Cornelius; Wegrzyn, David; Bauch, Juliane & Faissner, Andreas