TY  - JOUR
AU  - Dereddi, Ram R
AU  - Djannatian, Minou
AU  - Fiore, Frederic
AU  - Kalita, Darshana
AU  - Verkest, Clement
AU  - Torres, Felipe Bodaleo
AU  - Möbius, Wiebke
AU  - Khodaie, Babak
AU  - Ruhwedel, Torben
AU  - Alhalaseh, Khaleel
AU  - Schifferer, Martina
AU  - Wirth, Angela
AU  - Hill, Anthony
AU  - Ottenheijm, Roger
AU  - Patrizi, Annarita
AU  - Kann, Oliver
AU  - Lechner, Stefan G
AU  - Freichel, Marc
AU  - Agarwal, Amit
TI  - Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry.
JO  - Neuron
VL  - 114
IS  - 4
SN  - 0896-6273
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2026-00218
SP  - 699 - 723.e11
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Myelin Sheath: metabolism
KW  - Myelin Sheath: ultrastructure
KW  - Zebrafish
KW  - Mice
KW  - Mechanotransduction, Cellular: physiology
KW  - Oligodendroglia: metabolism
KW  - Oligodendroglia: ultrastructure
KW  - Axons: metabolism
KW  - Zebrafish Proteins: genetics
KW  - Zebrafish Proteins: metabolism
KW  - Calcium Signaling: physiology
KW  - Myelin Basic Protein: metabolism
KW  - Myelin Basic Protein: genetics
KW  - HLD19 (Other)
KW  - MBP transport (Other)
KW  - TMEM63A (Other)
KW  - axon-glia interactions (Other)
KW  - calcium signaling (Other)
KW  - mechanical forces (Other)
KW  - mechanotransduction channels (Other)
KW  - myelination (Other)
KW  - myosin5a (Other)
KW  - oligodendrocyte (Other)
KW  - transient infantile hypomyelinating leukodystrophy-19 (Other)
KW  - Zebrafish Proteins (NLM Chemicals)
KW  - Myelin Basic Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41483808
DO  - DOI:10.1016/j.neuron.2025.11.009
UR  - https://pub.dzne.de/record/285352
ER  -