PIEZOs regulate oligodendrocyte sheath formation, expansion, and myelination potential

Myelination requires precise integration of physical cues by oligodendrocyte lineage cells (OLCs), but the molecular sensors that detect these cues remain incompletely understood. Here, we demonstrate that oligodendrocyte progenitor cells (OPCs) are sensitive to sub-micron changes in membrane displacement. Based on channel properties, RNA expression, and protein abundance, we find that the mechanosensitive ion channel PIEZO1 contributes to OPC mechanosensitivity. In vivo, zebrafish with oligodendrocyte (OL)-specific disruption of piezo1 have fewer sheaths per OL. Zebrafish with OL-specific piezo2 disruption also have fewer sheaths as well as decreased total myelin capacity over time. OL-specific disruption of both piezo1 and piezo2 caused more severe phenotypes, with reduced OPC volume, and in myelinating OLs, reduced sheath number, sheath length, and total myelin output. Furthermore, piezo1/piezo2 disruption leads to sporadic sheath formation outside the normal developmental window. Our findings indicate that OLs use Piezo channels in vivo to influence sheath formation, expansion, and retractions.