Oligodendrocyte mechanosensitivity: translates geometric cues into myelin patterns?

Abstract

How oligodendrocytes (OLs) perceive the geometric features of axons and convert them into precise myelin structures remains unclear. The study by Dereddi et al. showed that the ion channel transmembrane protein 63A (TMEM63A) mediates the conversion of membrane tension at the contact site through activating intracellular Ca²⁺ signaling. This work demonstrates that TMEM63A is crucial for tuning myelin geometry, including thickness, length, and compatibility with axons. The deficiency of TMEM63A aligns with the clinical phenotype of human hypomyelinating leukodystrophy-19 (HLD19) syndrome. These findings provide new potential therapeutic targets for the intervention of diseases related to hypomyelinating disorders.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. W2511025).

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the work as follows: manuscript conception, revision, and supervision: Mei F; manuscript writing and figure creation: Si T. All authors reviewed and approved the final version of the manuscript.

Data availability

Data sharing is not applicable to this commentary as no datasets were generated or analyzed.

Conflict of interest

The authors declare that they have no conflict of interest.

References

[1] Taveggia C, Zanazzi G, Petrylak A, Yano H, Rosenbluth J, et al. 2005. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47: 681-694

[2] Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, et al. 2004. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304: 700-703

[3] Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Müller T, et al. 2008. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59: 581-595

[4] Lee S, Leach MK, Redmond SA, Christin Chong SY, Mellon SH, et al. 2012. A culture system to study oligodendrocyte myelination processes using engineered nanofibers. Nature Methods 9: 917-922

[5] Mei F, Fancy SPJ, Shen YAA, Niu J, Zhao C, et al. 2014. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature Medicine 20: 954-960

[6] Acheta J, Bhatia U, Haley J, Hong J, Rich K, et al. 2022. Piezo channels contribute to the regulation of myelination in Schwann cells. GLIA 70: 2276-2289

[7] Mayoral SR, Etxeberria A, Shen YA, Chan JR. 2018. Initiation of CNS myelination in the optic nerve is dependent on axon caliber. Cell Reports 25: 544-550.e3

[8] Segel M, Neumann B, Hill MFE, Weber IP, Viscomi C, et al. 2019. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573: 130-134

[9] Murthy SE, Dubin AE, Whitwam T, Jojoa-Cruz S, Cahalan SM, et al. 2018. OSCA/TMEM63 are an evolutionarily conserved family of mechanically activated ion channels. eLife 7: e41844

[10] Dereddi RR, Djannatian M, Fiore F, Kalita D, Verkest C, et al. 2026. Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry. Neuron 114: 699-723.e11

[11] Yan H, Helman G, Murthy SE, Ji H, Crawford J, et al. 2019. Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy. The American Journal of Human Genetics 105: 996-1004

[12] Iyer M, Kantarci H, Cooper MH, Ambiel N, Novak SW, et al. 2024. Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension. Nature Communications 15: 265

[13] Halford J, Senatore AJ, Berryman S, Muñoz A, Semidey D, et al. 2025. TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination. Proceedings of the National Academy of Sciences of the United States of America 122: e2507354122