Biozentrum of the University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
Department of Biomedicine, University of Basel, Pestalozzistrasse 20, 4056 Basel, Switzerland.
Neuron. 2022 Jul 6;110(13):2094-2109.e10. doi: 10.1016/j.neuron.2022.04.017. Epub 2022 May 11.
The diversification of cell adhesion molecules by alternative splicing is proposed to underlie molecular codes for neuronal wiring. Transcriptomic approaches mapped detailed cell-type-specific mRNA splicing programs. However, it has been hard to probe the synapse-specific localization and function of the resulting protein splice isoforms, or "proteoforms," in vivo. We here apply a proteoform-centric workflow in mice to test the synapse-specific functions of the splice isoforms of the synaptic adhesion molecule Neurexin-3 (NRXN3). We uncover a major proteoform, NRXN3 AS5, that is highly expressed in GABAergic interneurons and at dendrite-targeting GABAergic terminals. NRXN3 AS5 abundance significantly diverges from Nrxn3 mRNA distribution and is gated by translation-repressive elements. Nrxn3 AS5 isoform deletion results in a selective impairment of dendrite-targeting interneuron synapses in the dentate gyrus without affecting somatic inhibition or glutamatergic perforant-path synapses. This work establishes cell- and synapse-specific functions of a specific neurexin proteoform and highlights the importance of alternative splicing regulation for synapse specification.
通过选择性剪接使细胞黏附分子多样化，被认为是神经元连接的分子密码的基础。转录组学方法描绘了详细的细胞类型特异性 mRNA 剪接程序。然而，很难在体内探测到由此产生的蛋白质剪接异构体或“蛋白异构体”的突触特异性定位和功能。我们在这里应用一种以蛋白异构体为中心的工作流程在小鼠中测试突触粘附分子神经连接蛋白 3 (NRXN3) 的剪接异构体的突触特异性功能。我们发现了一种主要的蛋白异构体 NRXN3 AS5，它在 GABA 能中间神经元和靶向树突的 GABA 能末梢中高度表达。NRXN3 AS5 的丰度与 Nrxn3 mRNA 的分布显著不同，并且受到翻译抑制元件的调控。Nrxn3 AS5 异构体缺失导致齿状回中靶向树突的 GABA 能中间神经元突触选择性损伤，而不影响躯体抑制或谷氨酸能穿通通路突触。这项工作确立了特定神经连接蛋白异构体的细胞和突触特异性功能，并强调了选择性剪接调控对于突触特化的重要性。
