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Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as...

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Autores principales: Scott‐Hewitt, Nicole, Perrucci, Fabio, Morini, Raffaella, Erreni, Marco, Mahoney, Matthew, Witkowska, Agata, Carey, Alanna, Faggiani, Elisa, Schuetz, Lisa Theresia, Mason, Sydney, Tamborini, Matteo, Bizzotto, Matteo, Passoni, Lorena, Filipello, Fabia, Jahn, Reinhard, Stevens, Beth, Matteoli, Michela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429741/
https://www.ncbi.nlm.nih.gov/pubmed/32657463
http://dx.doi.org/10.15252/embj.2020105380
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author Scott‐Hewitt, Nicole
Perrucci, Fabio
Morini, Raffaella
Erreni, Marco
Mahoney, Matthew
Witkowska, Agata
Carey, Alanna
Faggiani, Elisa
Schuetz, Lisa Theresia
Mason, Sydney
Tamborini, Matteo
Bizzotto, Matteo
Passoni, Lorena
Filipello, Fabia
Jahn, Reinhard
Stevens, Beth
Matteoli, Michela
author_facet Scott‐Hewitt, Nicole
Perrucci, Fabio
Morini, Raffaella
Erreni, Marco
Mahoney, Matthew
Witkowska, Agata
Carey, Alanna
Faggiani, Elisa
Schuetz, Lisa Theresia
Mason, Sydney
Tamborini, Matteo
Bizzotto, Matteo
Passoni, Lorena
Filipello, Fabia
Jahn, Reinhard
Stevens, Beth
Matteoli, Michela
author_sort Scott‐Hewitt, Nicole
collection PubMed
description Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal “eat‐me” signal involved in microglial‐mediated pruning. In hippocampal neuron and microglia co‐cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS‐labeled material by microglia occurs during established developmental periods of microglial‐mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial‐mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.
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spelling pubmed-74297412020-08-18 Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia Scott‐Hewitt, Nicole Perrucci, Fabio Morini, Raffaella Erreni, Marco Mahoney, Matthew Witkowska, Agata Carey, Alanna Faggiani, Elisa Schuetz, Lisa Theresia Mason, Sydney Tamborini, Matteo Bizzotto, Matteo Passoni, Lorena Filipello, Fabia Jahn, Reinhard Stevens, Beth Matteoli, Michela EMBO J Articles Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal “eat‐me” signal involved in microglial‐mediated pruning. In hippocampal neuron and microglia co‐cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS‐labeled material by microglia occurs during established developmental periods of microglial‐mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial‐mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures. John Wiley and Sons Inc. 2020-07-13 2020-08-17 /pmc/articles/PMC7429741/ /pubmed/32657463 http://dx.doi.org/10.15252/embj.2020105380 Text en © 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Scott‐Hewitt, Nicole
Perrucci, Fabio
Morini, Raffaella
Erreni, Marco
Mahoney, Matthew
Witkowska, Agata
Carey, Alanna
Faggiani, Elisa
Schuetz, Lisa Theresia
Mason, Sydney
Tamborini, Matteo
Bizzotto, Matteo
Passoni, Lorena
Filipello, Fabia
Jahn, Reinhard
Stevens, Beth
Matteoli, Michela
Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title_full Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title_fullStr Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title_full_unstemmed Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title_short Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
title_sort local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429741/
https://www.ncbi.nlm.nih.gov/pubmed/32657463
http://dx.doi.org/10.15252/embj.2020105380
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