PDF(Pubmed)
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.
摘要：
神经元轴突的髓鞘形成对神经系统发育至关重要。髓鞘形成需要少突胶质细胞中戏剧性的细胞骨架动力学，但是肌动蛋白在髓鞘形成过程中是如何调节的，人们知之甚少。我们最近确定了血清反应因子（SRF）-一种已知在其他细胞类型中调节肌动蛋白和肌动蛋白调节剂表达的转录因子-作为老年大脑髓鞘形成的关键驱动因素。然而，在了解SRF在少突胶质细胞谱系细胞中的机制作用方面仍存在很大差距.这里,我们表明，SRF是少突胶质细胞在发育过程中髓鞘形成所必需的细胞自主功能。将ChIP-seq与RNA-seq组合鉴定少突胶质细胞前体细胞和少突胶质细胞中的SRF靶基因,其包括肌动蛋白和其他关键细胞骨架基因。因此，SRF敲除少突胶质细胞在分化早期表现出显著降低的肌动蛋白丝水平,与其在肌动蛋白依赖性髓鞘起始中的作用一致。令人惊讶的是,少突胶质细胞限制性的SRF损失导致与衰老和神经退行性疾病相关的基因标记的上调。一起,我们的发现将SRF确定为转录调节因子,它控制少突胶质细胞髓鞘形成所需的细胞骨架基因的表达.这项研究确定了调节少突胶质细胞生物学的重要途径，与大脑发育高度相关。老化，和疾病。
