The function of neuronal circuits relies on the properties of individual neuronal cells and their synapses. We propose that a substantial degree of synapse formation and function is instructed by molecular codes resulting from transcriptional programmes. Recent studies on the Neurexin protein family and its ligands provide fundamental insight into how synapses are assembled and remodelled, how synaptic properties are specified and how single gene mutations associated with neurodevelopmental and psychiatric disorders might modify the operation of neuronal circuits and behaviour. In this Review, we first summarize insights into Neurexin function obtained from various model organisms. We then discuss the mechanisms and logic of the cell type-specific regulation of Neurexin isoforms, in particular at the level of alternative mRNA splicing. Finally, we propose a conceptual framework for how combinations of synaptic protein isoforms act as ‘senders’ and ‘readers’ to instruct synapse formation and the acquisition of cell type-specific and synapse-specific functional properties.
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A.M.G. was financially supported by an advanced European Molecular Biology Organization (EMBO) long-term fellowship. L.T. was supported by the Boehringer Ingelheim Fonds and the Doris Dietschy and Denise Dietschy-Frick-Stiftung. Work in the laboratory of P.S. is supported by the Swiss National Science Foundation, a European Research Council Advanced Grant (SPLICECODE), and EU-AIMS and AIMS-2-TRIALS supported by the Innovative Medicines Initiatives from the European Commission. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associates (EFPIA), Autism Speaks, Autistica and the Simons Foundation Autism Research Initiative (SFARI).
The authors declare no competing interests.
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Nature Reviews Neuroscience thanks Michael Hart, who co-reviewed with Mara Cowen, Robin Hiesinger and the other anonymous reviewer for their contribution to the peer review of this work.
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- Alternative splicing
A process in which exons of an mRNA are assembled in multiple different (alternative) ways to yield multiple different versions of a final mRNA molecule that may contain different RNA regulatory motifs or encode alternative protein forms.
Variants of an mRNA transcript or protein generated from a single gene but differing in sequence (for example, resulting from alternative promoters or from alternative splicing).
- Post-translational modifications
Enzymatic chemical modifications of specific amino acids in a protein that occur in the cell after or during mRNA translation (for example, through phosphorylation, glycosylation, acetylation and so on).
- Structural motifs
Structurally conserved building blocks or ‘super-secondary structures’ that appear in various protein molecules that may or may not be functionally related.
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Gomez, A.M., Traunmüller, L. & Scheiffele, P. Neurexins: molecular codes for shaping neuronal synapses. Nat Rev Neurosci 22, 137–151 (2021). https://doi.org/10.1038/s41583-020-00415-7
Frontiers in Molecular Neuroscience (2021)