Alternative splicing of latrophilin-3 controls synapse formation

• 成果类型: Article
• 署名作者: Wang, Shuai; Deleon, Chelsea; Sun, Wenfei; Quake, Stephen R.; Roth, Bryan L.; Suedhof, Thomas C.
• 署名单位: Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; Stanford University; Chan Zuckerberg Initiative (CZI)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6645
• DOI: 10.1038/s41586-023-06913-9
• 发表日期: 2024-02-01
• 关键词: structural basis; cell-adhesion; receptor; RECOGNITION; molecules; interacts; proteins

摘要

The assembly and specification of synapses in the brain is incompletely understood1-3. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion G-protein-coupled receptor-mediates synapse formation in the hippocampus4 but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of G alpha s signalling and recruitment of phase-separated postsynaptic protein scaffolds. We found that cell-type-specific alternative splicing of Lphn3 controls the LPHN3 G-protein-coupling mode, resulting in LPHN3 variants that predominantly signal through G alpha s or G alpha 12/13. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a G alpha s- to a G alpha 12/13-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that G alpha s signalling by LPHN3 splice variants mediates synapse formation. Notably, G alpha s-coupled, but not G alpha 12/13-coupled, splice variants of LPHN3 also recruit phase-transitioned postsynaptic protein scaffold condensates, such that these condensates are clustered by binding of presynaptic teneurin and FLRT ligands to LPHN3. Moreover, neuronal activity promotes alternative splicing of the synaptogenic G alpha s-coupled variant of LPHN3. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways: G alpha s signalling and clustered phase separation of postsynaptic protein scaffolds. Latrophilin-3 organizes synapses through a convergent dual-pathway mechanism in which G alpha s signalling is activated and phase-separated postsynaptic protein scaffolds are recruited.