Journal Article

DZNE-2026-00218

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry.

Dereddi, R. R. ; Djannatian, M.DZNE* ; Fiore, F. ; Kalita, D. ; Verkest, C. ; Torres, F. B. ; Möbius, W. ; Khodaie, B. ; Ruhwedel, T. ; Alhalaseh, K. ; Schifferer, M.DZNE* ; Wirth, A. ; Hill, A. ; Ottenheijm, R. ; Patrizi, A. ; Kann, O. ; Lechner, S. G. ; Freichel, M. ; Agarwal, A.

2026
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Myelin Sheath: ultrastructure (MeSH) ; Zebrafish (MeSH) ; Mice (MeSH) ; Mechanotransduction, Cellular: physiology (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Oligodendroglia: ultrastructure (MeSH) ; Axons: metabolism (MeSH) ; Zebrafish Proteins: genetics (MeSH) ; Zebrafish Proteins: metabolism (MeSH) ; Calcium Signaling: physiology (MeSH) ; Myelin Basic Protein: metabolism (MeSH) ; Myelin Basic Protein: genetics (MeSH) ; HLD19 ; MBP transport ; TMEM63A ; axon-glia interactions ; calcium signaling ; mechanical forces ; mechanotransduction channels ; myelination ; myosin5a ; oligodendrocyte ; transient infantile hypomyelinating leukodystrophy-19 ; Zebrafish Proteins ; Myelin Basic Protein

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)
2. Neuronal Cell Biology (AG Misgeld)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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