The lysosomal cation channel TRPML1 regulates the oligodendrocyte cytoskeleton.

Differentiating oligodendrocytes undergo dramatic morphologic alterations to transition from progenitors to mature oligodendrocytes that synthesize myelin, the lipid-rich membrane coating axons which strengthens saltatory conduction and provides metabolic support. Actin dynamics, which are often regulated by membrane bound nucleators associated with organelles, underpin the morphologic shifts in oligodendrocyte maturation; however, the origin of such regulation during oligodendrocyte differentiation remains unknown. Here, we demonstrate that the lysosomal non-selective cation channel, transient potential mucolipin 1 (TRPML1), is a critical regulator of oligodendrocyte morphology during differentiation and initial myelination. Lysosomes move into oligodendrocyte processes during differentiation. While manipulation of TRPML1 did not change the expression of oligodendrocyte lineage markers, activation of TRPML1 resulted in altered oligodendrocyte morphology and an increase in actin filament content driven by the small GTPase Rac1 and subsequent disinhibition of PAK1 via phosphorylation. Actin associated changes in morphology are accompanied by the presence of lysosomal-derived calcium transients in nascent oligodendrocyte processes, potentially revealing a link between localized calcium signaling and actin polymerization. Lastly, adolescent mice (