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Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition
David Hauser1, Katharina Behr2, Kohtarou Konno3
1Biozentrum of the University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
Neuron
|May 13, 2022
Summary
Alternative splicing creates diverse protein isoforms (proteoforms) crucial for neuronal wiring. This study reveals a specific Neurexin-3 proteoform
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alternative splicing diversifies cell adhesion molecules, potentially forming molecular codes for neuronal wiring.
- Transcriptomics reveals cell-type-specific splicing but probing protein splice isoform (proteoform) function in vivo remains challenging.
Purpose of the Study:
- To investigate the synapse-specific functions of Neurexin-3 (NRXN3) splice isoforms using a proteoform-centric approach in mice.
- To determine the role of specific NRXN3 proteoforms in neuronal connectivity and synaptic function.
Main Methods:
- Developed and applied a proteoform-centric workflow in mice.
- Analyzed NRXN3 splice isoform expression, localization, and function.
- Utilized genetic deletion of specific Nrxn3 proteoforms.
Main Results:
- Identified NRXN3 AS5 as a major proteoform highly expressed in GABAergic interneurons and at dendrite-targeting GABAergic terminals.
- NRXN3 AS5 abundance showed divergence from Nrxn3 mRNA levels, regulated by translational repression.
- Deletion of NRXN3 AS5 selectively impaired dendrite-targeting interneuron synapses in the dentate gyrus.
Conclusions:
- Established cell- and synapse-specific functions for a Neurexin-3 proteoform.
- Highlighted the critical role of alternative splicing regulation in synapse specification.
- Demonstrated the importance of proteoform-level analysis for understanding neuronal function.
