Astrocyte-derived small extracellular vesicles promote synapse formation via fibulin-2-mediated TGF-β signaling

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (10), p.108829-108829, Article 108829
• Main Authors: Patel, Mikin R., Weaver, Alissa M.
• Format: Article
• Language: English
• Subjects: Animals; Astrocyte-derived small extracellular vesicles; Astrocytes - cytology; Astrocytes - metabolism; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cells, Cultured; Dendritic Spines - physiology; Extracellular Matrix Proteins - antagonists & inhibitors; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Extracellular Vesicles - metabolism; Female; fibulin-2; HSP70 Heat-Shock Proteins - metabolism; Humans; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Recombinant Proteins - biosynthesis; Recombinant Proteins - pharmacology; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Smad2 Protein - metabolism; Synapses - physiology; synaptogenesis; TGF-β signaling; Transforming Growth Factor beta - metabolism
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Astrocyte-derived small EVs (SEVs) enhance neuronal spine and synapse formation•Fibulin-2 is a key synaptogenic cargo present on astrocyte-derived SEVs•Astrocyte SEVs and fibulin-2 activate TGF-β signaling in neurons•Astrocyte SEV- and fibulin-2-driven synaptogenesis depend on TGF-β signaling Patel and Weaver provide evidence for the function of astrocyte-derived small extracellular vesicles (SEVs) in synaptogenesis of primary cortical neurons. Astrocyte-derived SEVs carry fibulin-2 on the surface of SEVs that leads to activation of TGF-β signaling in neurons. The fibulin-2-driven TGF-β signaling drives dendritic spine and synapse formation.