Significance
Myelin is essential for the development and function of the central nervous system (CNS), and its loss or dysfunction is central to aging and neurodegenerative diseases. To build myelin, oligodendrocytes undergo dramatic cell morphology changes that are powered by actin cytoskeletal dynamics. However, how the oligodendrocyte cytoskeleton is regulated during myelination remains poorly understood. Here, we identify the transcription factor SRF (serum response factor) as essential for myelination. SRF directly regulates expression of actin regulatory genes in oligodendrocytes and, surprisingly, also inhibits disease-associated gene expression. Together with our recent discovery that SRF promotes oligodendrocyte rejuvenation, our findings uncover a pathway promoting myelin formation that may represent a therapeutic target for restoring myelin in the aged or diseased CNS.
Abstract
Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
