Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition

Hauser, David and Behr, Katharina and Konno, Kohtarou and Schreiner, Dietmar and Schmidt, Alexander and Watanabe, Masahiko and Bischofberger, Josef and Scheiffele, Peter. (2022) Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition. Neuron, 110 (13). pp. 2094-2109.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Scheiffele)
UniBasel Contributors:Scheiffele, Peter
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Jul 2022 14:36
Deposited On:19 Jul 2022 14:36

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