美国斯坦福大学Thomas C. Südhof等研究人员合作发现，latrophilin-3的可变剪接控制突触的形成。该研究于2024年1月17日在线发表于国际一流学术期刊《自然》。

研究人员表示，人们对大脑中突触的装配和特化尚不完全了解。突触后粘附G蛋白偶联受体Latrophilin-3（由Adgrl3编码，又称Lphn3）介导海马中突触的形成，但其中的机制仍不清楚。

研究人员在小鼠身上发现，LPHN3通过一种趋同的双途径机制组织突触：激活Gαs信号和招募相分离的突触后蛋白支架。研究人员发现，Lphn3的细胞类型特异性替代剪接控制着LPHN3的G蛋白偶联模式，从而产生了主要通过Gα_s或Gα_12/13发出信号的LPHN3变体。CRISPR介导的Lphn3可变剪接操作使LPHN3从Gα_s耦合模式转变为Gα_12/13耦合模式，其损害突触连接性的严重程度不亚于Lphn3的整体缺失，这表明LPHN3剪接变体的Gα_s信号介导了突触的形成。

值得注意的是，Gα_s耦合（而非Gα_12/13耦合）的LPHN3剪接变体也能招募突触后蛋白支架凝集物，这些凝集物通过突触前teneurin和FLRT配体与LPHN3的结合而聚集在一起。此外，神经元活动会促进突触生成的Gα_s偶联变体LPHN3的可变剪接。这些数据共同表明，一种关键突触粘附分子的活动依赖性可变剪接通过平行激活两种趋同途径来控制突触的形成：Gα_s信号和突触后蛋白质支架的成簇相分离。

附：英文原文

Title: Alternative splicing of latrophilin-3 controls synapse formation

Author: Wang, Shuai, DeLeon, Chelsea, Sun, Wenfei, Quake, Stephen R., Roth, Bryan L., Sdhof, Thomas C.

Issue&Volume: 2024-01-17

Abstract: 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 Gαs 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 Gαs or Gα12/13. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a Gαs- to a Gα12/13-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that Gαs signalling by LPHN3 splice variants mediates synapse formation. Notably, Gαs-coupled, but not Gα12/13-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 Gαs-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: Gαs signalling and clustered phase separation of postsynaptic protein scaffolds. Latrophilin-3 organizes synapses through a convergent dual-pathway mechanism in which Gαs signalling is activated and phase-separated postsynaptic protein scaffolds are recruited.

DOI: 10.1038/s41586-023-06913-9

Source: https://www.nature.com/articles/s41586-023-06913-9