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Abstract

TMEM63A functions as a key mechanosensitive channel in oligodendrocytes (OLs), crucial for their maturation and developmental myelination. Through high-resolution confocal, STED, and immuno-electron microscopy, I show that TMEM63A localizes to myelin membranes, OL processes, and endo-lysosomal compartments. Loss of TMEM63A in mice results in stage-specific hypomyelination and delayed OL differentiation, leading to transient myelin deficits during early postnatal development that partially recover by 5 weeks of age. This phenotype mirrors the human TMEM63A-associated hypomyelinating leukodystrophy (HLD19). Despite gross recovery of myelination, ultrastructural analyses reveal persistent defects, including abnormal node–internode architecture, hypomyelination of large-caliber axons, inappropriate myelination of small-caliber axons, and fine motor impairments. Conditional knockout experiments demonstrate that TMEM63A acts cell-autonomously in OLs to control their maturation and myelin sheath formation. Transcriptomic analyses further reveal downregulation of Myo5a and reduced MYO5A protein levels in TMEM63A-deficient OLs, accompanied by impaired Mbp mRNA transport and reduced myelin basic protein synthesis. Together, these findings establish TMEM63A as a critical mechanotransduction channel that links mechanical cues to intracellular signaling pathways governing Mbp mRNA trafficking and myelin formation.