Sept7 coordinates cytoskeletal dynamics and MAPK/ERK1/2 signaling to orchestrate OPC differentiation and myelination

Abstract Age-related neurodegenerative diseases like Alzheimer’s disease are often associated with white matter damage, which may even initiate pathogenesis. Oligodendrocytes (OLs)—the myelin-forming cells—arise from oligodendrocyte precursor cells (OPCs) through a differentiation process tightly governed by actin and microtubule dynamics. Septin 7 (Sept7), an essential septin cytoskeletal component, is expressed in OLs and downregulated in aging and dysmyelination models, yet its mechanistic role in myelination remains unclear. Here we show that Sept7 orchestrates cytoskeletal remodeling by regulating cofilin‑dependent actin turnover and microtubule plasticity, enabling the morphological changes required for OPC differentiation. Sept7 physically associates with core MAPK/ERK1/2 signaling components, suggesting a scaffolding function. Loss of Sept7 selectively impairs ERK1/2 activation and reduces expression of key myelinogenic transcription factors, resulting in defective OPC differentiation and myelination. Our findings reveal a critical link between Sept7, cytoskeletal dynamics, and MAPK signaling in OL maturation, and provide mechanistic insight into myelin degeneration triggered by aging or pathological insults, with implications for the pathogenesis and progression of central nervous system (CNS) degenerative diseases.