Alternative splicing of latrophilin-3 controls synapse formation.
Alternative splicing of latrophilin-3 controls synapse formation.
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DOI：
10.1038/s41586-023-06913-9
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发表时间：
2024-02
期刊：
影响因子：
64.8
通讯作者：
Suedhof, Thomas C.
中科院分区：
文献类型：
--
作者：
Wang, Shuai;Deleon, Chelsea;Sun, Wenfei;Quake, Stephen R.;Roth, Bryan L.;Suedhof, Thomas C.
大脑中突触的组装和规范尚未完全被理解。Latrophilin - 3（由Adgrl3编码，也称为Lphn3）——一种突触后黏附G蛋白偶联受体——介导海马体中的突触形成，但相关机制仍不清楚。在此我们在小鼠中表明，LPHN3通过一种汇聚的双通路机制来组织突触：Gαs信号的激活以及相分离的突触后蛋白质支架的募集。我们发现Lphn3的细胞类型特异性可变剪接控制LPHN3的G蛋白偶联模式，导致LPHN3变体主要通过Gαs或Gα12/13进行信号传导。通过CRISPR对Lphn3可变剪接的操作，使LPHN3从Gαs偶联模式转变为Gα12/13偶联模式，这与Lphn3的整体缺失一样严重地损害了突触连接性，表明LPHN3剪接变体的Gαs信号传导介导突触形成。值得注意的是，LPHN3的Gαs偶联而非Gα12/13偶联的剪接变体也募集发生相变的突触后蛋白质支架凝聚物，使得这些凝聚物通过突触前的腱蛋白和FLRT配体与LPHN3的结合而聚集。此外，神经元活动促进LPHN3的促突触形成的Gαs偶联变体的可变剪接。总之，这些数据表明，一个关键的突触黏附分子的活动依赖性可变剪接通过两条汇聚通路的平行激活来控制突触形成：Gαs信号传导以及突触后蛋白质支架的聚集相分离。
Latrophilin - 3通过一种汇聚的双通路机制组织突触，在该机制中Gαs信号被激活，并且相分离的突触后蛋白质支架被募集。
The assembly and specification of synapses in the brain is incompletely understood. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)—a postsynaptic adhesion G-protein-coupled receptor—mediates synapse formation in the hippocampus 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.
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影响因子：
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