Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Rep. 2021 Mar 9;34(10):108829. doi: 10.1016/j.celrep.2021.108829.
Neuronal synapse formation is critical for brain development and depends on secreted factors from astrocytes. Here, we report that small extracellular vesicles (EVs) secreted from primary astrocytes, but not from neurons or C6 glioma cells, greatly enhance spine and synapse formation by primary cortical neurons. A comparative proteomics analysis of small EVs from astrocytes, neurons, and C6 glioma cells identified fibulin-2 as a promising EV cargo to regulate synaptogenesis. Treatment of cortical neurons with recombinant fibulin-2 increased the formation of spines and synapses, similar to the effect of small EVs. In addition, treatment of neurons with fibulin-2 or astrocyte-derived small EVs led to increased phosphorylation of Smad2, an indicator of TGF-β signaling. Finally, the effects of fibulin-2 and astrocyte-derived small EVs on synapse formation were reversed by inhibiting transforming growth factor β (TGF-β) signaling. These data suggest a model in which astrocyte EVs promote synapse formation via fibulin-2-mediated activation of TGF-β signaling.
神经元突触的形成对于大脑发育至关重要，并且依赖于星形胶质细胞分泌的因子。在这里，我们报告从小鼠原代星形胶质细胞分泌的小细胞外囊泡（EVs）而非神经元或 C6 神经胶质瘤细胞分泌的小细胞外囊泡极大地增强了原代皮质神经元的突棘和突触的形成。对星形胶质细胞、神经元和 C6 神经胶质瘤细胞来源的小 EVs 的比较蛋白质组学分析鉴定出纤连蛋白-2 是一种有前途的 EV 货物，可调节突触发生。用重组纤连蛋白-2 处理皮质神经元会增加突棘和突触的形成，这与小 EVs 的作用相似。此外，用纤连蛋白-2 或星形胶质细胞来源的小 EVs 处理神经元会导致 Smad2 的磷酸化增加，Smad2 是 TGF-β信号的指标。最后，通过抑制转化生长因子β（TGF-β）信号，纤连蛋白-2 和星形胶质细胞来源的小 EVs 对突触形成的作用被逆转。这些数据表明，星形胶质细胞 EV 通过纤连蛋白-2 介导的 TGF-β信号激活促进突触形成的模型。
