Polarized targeting of neurexins to synapses is regulated by their C-terminal sequences
Open accessAbstract
Two families of cell-adhesion molecules, predominantly presynaptic neurexins and postsynaptic neuroligins, are important for the formation and functioning of synapses in the brain, and mutations in several genes encoding these transmembrane proteins have been found in autism patients. However, very little is known about how neurexins are targeted to synapses and which mechanisms regulate this process. Using various epitope-tagged neurexins in primary hippocampal neurons of wild-type and knock-out mice in vitro and in transgenic animals in vivo, we show that neurexins are trafficked throughout neurons via transport vesicles and the plasma membrane insertion of neurexins occurs preferentially in the axonal/synaptic compartment. We also observed that exit of neurexins from the ER/Golgi and correct targeting require their PDZ-binding motif at the C terminus, whereas two presumptive ER retention signals are inactive. The ubiquitous presence of neurexin-positive transport vesicles and absence of bassoon colabeling demonstrate that these carriers are not active zone precursor vesicles, but colocalization with CASK, RIM1α, and calcium channels suggests that they may carry additional components of the exocytotic machinery. Our data indicate that neurexins are delivered to synapses by a polarized and regulated targeting process that involves PDZ-domain mediated interactions, suggesting a novel pathway for the distribution of neurexins and other synaptic proteins.
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CASK binds NRXN1 presynaptically, but its binding to TBR1 occurs in the nucleus.
“whereas CASK binds NRXN1 presynaptically [82], binding to the transcription factor TBR1 is in the nucleus [83].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [82]
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A de novo convergence of autism genetics and molecular neuroscience
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Retracted
- Authors
- Fairless, R., Masius, H., Rohlmann, A., Heupel, K., Ahmad, M., Reissner, C., Dresbach, T., & Missler, M.
- Affiliations
- University of Münster (DE)
- Heidelberg University (DE)
- Corresponding author
- Missler, Markus
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-26
- Volume
- 28
- Issue
- 48
- Pages
- 12969-12981
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671796
- OpenAlex
- W2094046408
- Cited by
- 91
- References
- 51
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 8 · 2012: 4
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 629)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- neurexin, synaptic targeting, PDZ-binding motif, C-terminal sequence, adhesion molecules, neuroligins, ER retention signal, transport vesicles, axonal transport, autism spectrum disorder, hippocampal neurons, exocytosis, bassoon, CASK, calcium channels
- MeSH terms
- Animals, Calcium-Binding Proteins, Cell Compartmentation, Cell Membrane, Cells, Cultured, Endoplasmic Reticulum, Golgi Apparatus, Hippocampus, Mice, Transgenic, Synapses, Synaptic Membranes, Calcium Channels, Cell Polarity, Protein Structure, Tertiary, Presynaptic Terminals, Mice, Knockout, Neural Cell Adhesion Molecules, GTP-Binding Proteins, Protein Transport, Transport Vesicles, Mice, Guanylate Kinases
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