2026
Neuron

Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry

Authors:

Ram R. Dereddi, Minou Djannatian, Frederic Fiore, Darshana Kalita, Clement Verkest, Felipe Bodaleo Torres, Wiebke Möbius, Babak Khodaie, Torben Ruhwedel, Khaleel Alhalaseh, Martina Schifferer, Angela Wirth, Anthony Hill, Roger Ottenheijm, Annarita Patrizi, Oliver Kann, Stefan G. Lechner, Marc Freichel, Amit Agarwal

Keywords:

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

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.