Myelin formation is a multistep process that is controlled by a number of different extracellular factors. During the development of the central nervous system (CNS), oligodendrocyte progenitor cells differentiate into mature oligodendrocytes that start to enwrap axons with myelin membrane sheaths after receiving the appropriate signal(s) from the axon or its microenvironment. The signals required to initiate this process are unknown. Here, we show that oligodendrocytes secrete small membrane vesicles, exosome-like vesicles, into the extracellular space that inhibit both the morphological differentiation of oligodendrocytes and myelin formation. The inhibitory effects of exosome-like vesicles were prevented by treatment with inhibitors of actomyosin contractility. Importantly, secretion of exosome-like vesicles from oligodendrocytes was dramatically reduced when cells were incubated by conditioned neuronal medium.In conclusion, our results provide new evidence for small and diffusible oligodendroglial-derived vesicular carriers within the extracellular space that have inhibitory properties on cellular growth. We propose that neurons control the secretion of autoinhibitory oligodendroglial-derived exosomes to coordinate myelin membrane biogenesis.During the development of the CNS, oligodendrocyte precursor cells (OPCs) 2 undergo major changes in cell morphology when they start to differentiate into myelin-forming oligodendrocytes (1-3). First, a large network of branching processes is formed, and then oligodendrocytes start to extend massive amounts of myelin membrane sheaths (4, 5). The generation of myelinating oligodendrocytes from proliferating, immature OPCs is complex and depends on an intrinsic genetic differentiation program that is regulated in part by an intracellular molecular clock determining how many times an OPC can divide before differentiating (6 -8). This intrinsic program is under the control of various extrinsic factors present within the microenvironment of oligodendrocytes. Many of these factors such as Notch1, Wnt, LINGO-1 (leucine-rich repeat, and Ig domain-containing, Nogo receptor-interacting protein 1), or the polysialylated neural cell adhesion molecule are inhibitory in nature and prevent OPCs from differentiating into mature oligodendrocytes (9 -14). Down-regulation of these inhibitory cues seems to be an important mechanism in triggering the differentiation of oligodendrocytes. Once differentiation of oligodendrocytes is induced, the cells start to synthesize large amount of myelin membrane components including lipids and several myelinspecific proteins, the major ones of these being the proteolipid protein (PLP) and the myelin basic proteins (MBP). Curiously, the biosynthesis of the major myelin membrane components occurs before the assembly of myelin is initiated, most likely by neuronal factor(s). In fact, such premyelinating oligodendrocytes that have started to synthesize myelin lipids and proteins but have not yet wrapped myelin around axons are only found for a relatively s...

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