Abstract
Synapse development requires spatiotemporally regulated recruitment of synaptic proteins. In this study, we describe a novel presynaptic mechanism of cis-regulated oligomerization of adhesion molecules that controls synaptogenesis. We identified synaptic adhesion-like molecule 1 (SALM1) as a constituent of the proposed presynaptic Munc18/CASK/Mint1/Lin7b organizer complex. SALM1 preferentially localized to presynaptic compartments of excitatory hippocampal neurons. SALM1 depletion in excitatory hippocampal primary neurons impaired Neurexin1β- and Neuroligin1-mediated excitatory synaptogenesis and reduced synaptic vesicle clustering, synaptic transmission, and synaptic vesicle release. SALM1 promoted Neurexin1β clustering in an F-actin- and PIP2-dependent manner. Two basic residues in SALM1's juxtamembrane polybasic domain are essential for this clustering. Together, these data show that SALM1 is a presynaptic organizer of synapse development by promoting F-actin/PIP2-dependent clustering of Neurexin.
Original language | English |
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Article number | e101289 |
Pages (from-to) | 1-20 |
Number of pages | 20 |
Journal | EMBO Journal |
Volume | 38 |
Issue number | 17 |
Early online date | 1 Aug 2019 |
DOIs | |
Publication status | Published - 2 Sept 2019 |
Bibliographical note
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.Funding
We thank Ingrid Saarloos, Robbert Zalm, and Joost Hoetjes for cloning, producing viral particles, and providing HEK cell cultures; Desiree Schut and Frank den Oudsten for providing primary neuron cultures; Joke Wortel for animal breeding; Rien Dekker for EM microscopy and analysis (the EM facility is supported by ZonMW 91111009); Jurjen Broeke for technical assistance with confocal microscopy; we thank all members of the Verhage laboratory for helpful discussions. We thank Synaptic Systems for providing SALM1 antibody. We thank Joris de Wit and Josh Huang for generously providing tagged Neurexin1β plasmid. This work is supported by an ERC Advanced Grant (322966) of the European Union (to MV). We thank Ingrid Saarloos, Robbert Zalm, and Joost Hoetjes for cloning, producing viral particles, and providing HEK cell cultures; Desiree Schut and Frank den Oudsten for providing primary neuron cultures; Joke Wortel for animal breeding; Rien Dekker for EM microscopy and analysis (the EM facility is supported by ZonMW 91111009); Jurjen Broeke for technical assistance with confocal microscopy; we thank all members of the Verhage laboratory for helpful discussions. We thank Synaptic Systems for providing SALM1 antibody. We thank Joris de Wit and Josh Huang for generously providing tagged Neurexin1? plasmid. This work is supported by an ERC Advanced Grant (322966) of the European Union (to MV).
Funders | Funder number |
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Seventh Framework Programme | 322966 |
European Commission | |
European Research Council | |
ZonMw | 91111009 |
Keywords
- Actins/metabolism
- Animals
- Calcium-Binding Proteins/metabolism
- Cell Adhesion Molecules, Neuronal/metabolism
- Cells, Cultured
- HEK293 Cells
- Hippocampus/cytology
- Humans
- Membrane Glycoproteins/genetics
- Mice
- Nerve Tissue Proteins/genetics
- Neural Cell Adhesion Molecules/metabolism
- Neurogenesis
- Phosphatidylinositol 4,5-Diphosphate/metabolism
- Synapses/metabolism