2. Academic Validation
  3. Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry

Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry

  • Neuron. 2026 Feb 18;114(4):699-723.e11. doi: 10.1016/j.neuron.2025.11.009.
Ram R Dereddi 1,  Minou Djannatian 2,  Frederic Fiore 3,  Darshana Kalita 3,  Clement Verkest 4,  Felipe Bodaleo Torres 3,  Wiebke Möbius 5,  Babak Khodaie 6,  Torben Ruhwedel 5,  Khaleel Alhalaseh 3,  Martina Schifferer 7,  Angela Wirth 8,  Anthony Hill 9,  Roger Ottenheijm 8,  Annarita Patrizi 9,  Oliver Kann 10,  Stefan G Lechner 4,  Marc Freichel 8,  Amit Agarwal 11
Affiliations

Affiliations

  • 1 Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany.
  • 2 Department of Neurology, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 3 Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.
  • 4 Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 5 Department of Neurogenetics and Electron Microscopy Unit, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, Germany.
  • 6 Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
  • 7 German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 8 Institute of Pharmacology, Heidelberg University, Heidelberg, Germany; German Centre for Cardiovascular Research (DZHK), Heidelberg, Germany.
  • 9 Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany; Schaller Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 10 Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany; Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
  • 11 Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany. Electronic address: [email protected].
PMID: 41483808 DOI: 10.1016/j.neuron.2025.11.009
Abstract

Oligodendrocytes, the myelinating cells of the central nervous system, precisely sculpt their insulating membranes to match axon size, ensuring fine-tuned action potential propagation. How oligodendrocytes estimate axon caliber to adapt myelin sheath geometry is unknown. The biochemical measure of axonal size provided by neuregulin 1 for Schwann cells is dispensable in oligodendrocytes, and we reasoned that biophysical cues might instead be required. By combining transcriptomics, in vivo optical imaging, and electron microscopy in mouse and zebrafish models, we identified TMEM63A as a key mechanosensitive channel in oligodendrocytes. TMEM63A enabled oligodendrocytes to sense membrane stretch and translate it into CA2+ signals. In the absence of TMEM63A, developmental myelination was severely impaired with shorter and thinner myelin sheaths on large-diameter axons, ectopic myelination of very small-diameter axons, and increased sheath retractions. We propose MYO5A-dependent Mbp mRNA targeting to the nascent myelin sheaths as a mechanism linking stretch-activated CA2+ signaling to myelin formation and sheath geometry refinement.

Keywords

HLD19; MBP transport; TMEM63A; axon-glia interactions; calcium signaling; mechanical forces; mechanotransduction channels; myelination; myosin5a; oligodendrocyte; transient infantile hypomyelinating leukodystrophy-19.

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