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Engineered adhesion molecules drive synapse organization

In multicellular organisms, cell-adhesion molecules connect cells into tissues and mediate intercellular signaling between these cells. In vertebrate brains, synaptic cell-adhesion molecules (SAMs) guide the formation, specification, and plasticity of synapses. Some SAMs, when overexpressed in cultu...

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Detalles Bibliográficos
Autores principales: Hale, W. Dylan, Südhof, Thomas C., Huganir, Richard L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934208/
https://www.ncbi.nlm.nih.gov/pubmed/36638214
http://dx.doi.org/10.1073/pnas.2215905120
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author Hale, W. Dylan
Südhof, Thomas C.
Huganir, Richard L.
author_facet Hale, W. Dylan
Südhof, Thomas C.
Huganir, Richard L.
author_sort Hale, W. Dylan
collection PubMed
description In multicellular organisms, cell-adhesion molecules connect cells into tissues and mediate intercellular signaling between these cells. In vertebrate brains, synaptic cell-adhesion molecules (SAMs) guide the formation, specification, and plasticity of synapses. Some SAMs, when overexpressed in cultured neurons or in heterologous cells co-cultured with neurons, drive formation of synaptic specializations onto the overexpressing cells. However, genetic deletion of the same SAMs from neurons often has no effect on synapse numbers, but frequently severely impairs synaptic transmission, suggesting that most SAMs control the function and plasticity of synapses (i.e., organize synapses) instead of driving their initial establishment (i.e., make synapses). Since few SAMs were identified that mediate initial synapse formation, it is difficult to develop methods that enable experimental control of synaptic connections by targeted expression of these SAMs. To overcome this difficulty, we engineered novel SAMs from bacterial proteins with no eukaryotic homologues that drive synapse formation. We named these engineered adhesion proteins “Barnoligin” and “Starexin” because they were assembled from parts of Barnase and Neuroligin-1 or of Barstar and Neurexin3β, respectively. Barnoligin and Starexin robustly induce the formation of synaptic specializations in a specific and directional manner in cultured neurons. Synapse formation by Barnoligin and Starexin requires both their extracellular Barnase- and Barstar-derived interaction domains and their Neuroligin- and Neurexin-derived intracellular signaling domains. Our findings support a model of synapse formation whereby trans-synaptic interactions by SAMs drive synapse organization via adhesive interactions that activate signaling cascades.
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spelling pubmed-99342082023-02-17 Engineered adhesion molecules drive synapse organization Hale, W. Dylan Südhof, Thomas C. Huganir, Richard L. Proc Natl Acad Sci U S A Biological Sciences In multicellular organisms, cell-adhesion molecules connect cells into tissues and mediate intercellular signaling between these cells. In vertebrate brains, synaptic cell-adhesion molecules (SAMs) guide the formation, specification, and plasticity of synapses. Some SAMs, when overexpressed in cultured neurons or in heterologous cells co-cultured with neurons, drive formation of synaptic specializations onto the overexpressing cells. However, genetic deletion of the same SAMs from neurons often has no effect on synapse numbers, but frequently severely impairs synaptic transmission, suggesting that most SAMs control the function and plasticity of synapses (i.e., organize synapses) instead of driving their initial establishment (i.e., make synapses). Since few SAMs were identified that mediate initial synapse formation, it is difficult to develop methods that enable experimental control of synaptic connections by targeted expression of these SAMs. To overcome this difficulty, we engineered novel SAMs from bacterial proteins with no eukaryotic homologues that drive synapse formation. We named these engineered adhesion proteins “Barnoligin” and “Starexin” because they were assembled from parts of Barnase and Neuroligin-1 or of Barstar and Neurexin3β, respectively. Barnoligin and Starexin robustly induce the formation of synaptic specializations in a specific and directional manner in cultured neurons. Synapse formation by Barnoligin and Starexin requires both their extracellular Barnase- and Barstar-derived interaction domains and their Neuroligin- and Neurexin-derived intracellular signaling domains. Our findings support a model of synapse formation whereby trans-synaptic interactions by SAMs drive synapse organization via adhesive interactions that activate signaling cascades. National Academy of Sciences 2023-01-13 2023-01-17 /pmc/articles/PMC9934208/ /pubmed/36638214 http://dx.doi.org/10.1073/pnas.2215905120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Hale, W. Dylan
Südhof, Thomas C.
Huganir, Richard L.
Engineered adhesion molecules drive synapse organization
title Engineered adhesion molecules drive synapse organization
title_full Engineered adhesion molecules drive synapse organization
title_fullStr Engineered adhesion molecules drive synapse organization
title_full_unstemmed Engineered adhesion molecules drive synapse organization
title_short Engineered adhesion molecules drive synapse organization
title_sort engineered adhesion molecules drive synapse organization
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934208/
https://www.ncbi.nlm.nih.gov/pubmed/36638214
http://dx.doi.org/10.1073/pnas.2215905120
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