Reciprocal control of excitatory synapse numbers by Wnt and Wnt inhibitor PRR7 secreted on exosomes

Nature Communications
Sang H LeeQing-Song Liu

Abstract

Secreted Wnts play crucial roles in synaptogenesis and synapse maintenance, but endogenous factors promoting synapse elimination in central neurons remain unknown. Here we show that proline-rich 7 (PRR7) induces specific removal of excitatory synapses and acts as a Wnt inhibitor. Remarkably, transmembrane protein PRR7 is activity-dependently released by neurons via exosomes. Exosomal PRR7 is uptaken by neurons through membrane fusion and eliminates excitatory synapses in neighboring neurons. Conversely, PRR7 knockdown in sparse neurons greatly increases excitatory synapse numbers in all surrounding neurons. These non-cell autonomous effects of PRR7 are effectively negated by augmentation or blockade of Wnt signaling. PRR7 exerts its effect by blocking the exosomal secretion of Wnts, activation of GSK3β, and promoting proteasomal degradation of PSD proteins. These data uncover a proximity-dependent, reciprocal mechanism for the regulation of excitatory synapse numbers in local neurons and demonstrate the significance of exosomes in inter-neuronal signaling in the vertebrate brain.

References

Jan 5, 2005·Biochemical and Biophysical Research Communications·Yasunobu MurataYoshinori Fujiyoshi
Feb 1, 2006·Molecular and Cellular Neurosciences·J FauréR Sadoul
Feb 28, 2006·The Journal of Biological Chemistry·Jianyong ChenShao-Jun Tang
Apr 4, 2006·Nature Neuroscience·Kenichi N HartmanVenkatesh N Murthy
Jul 14, 2006·Proceedings of the National Academy of Sciences of the United States of America·Lawrence RajendranKai Simons
Feb 7, 2007·Annual Review of Neuroscience·Veronica A Alvarez, Bernardo L Sabatini
Mar 3, 2007·Neuron·Stéphane PeineauGraham L Collingridge
Jan 30, 2008·Current Protocols in Cell Biology·Clotilde ThéryAled Clayton
Apr 1, 2009·The Journal of Biological Chemistry·Ginny G FaríasNibaldo C Inestrosa
Jun 6, 2009·Nature Reviews. Immunology·Clotilde ThéryElodie Segura
Aug 21, 2009·Nature Reviews. Neuroscience·Anthony Holtmaat, Karel Svoboda
Oct 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jiang FuWei Hsu
Dec 8, 2009·Nature Cell Biology·Matias OstrowskiClotilde Thery
Jun 25, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Loreto CuitinoNibaldo C Inestrosa
Sep 16, 2010·The Journal of Biological Chemistry·Bin SongMingtao Li
Nov 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lorena Varela-NallarNibaldo C Inestrosa
Nov 30, 2010·Molecular and Cellular Neurosciences·Gaelle LachenalRémy Sadoul
Dec 22, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shiva K TyagarajanJean-Marc Fritschy
Feb 25, 2011·Nature Neuroscience·Peter PenzesKevin M Woolfrey
Jun 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lorenza CianiPatricia C Salinas
Mar 9, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Silvia A PurroPatricia C Salinas
Mar 23, 2012·The Journal of Biological Chemistry·Kate KolesVivian Budnik
Jul 17, 2012·Trends in Molecular Medicine·Patrick HerrKonrad Basler
Jul 17, 2012·Trends in Neurosciences·Marcello D'AmelioFrancesco Cecconi
Sep 18, 2012·Nature Cell Biology·Julia Christina GrossMichael Boutros
Oct 23, 2012·Cold Spring Harbor Perspectives in Biology·Cristina-Maria Cruciat, Christof Niehrs
Jul 19, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Christopher D NelsonMorgan Sheng
Nov 14, 2013·Frontiers in Cellular Neuroscience·Ellen M Dickins, Patricia C Salinas
Nov 16, 2014·Journal of Extracellular Vesicles·Mathilde ChivetRémy Sadoul
Feb 20, 2016·Nature Reviews. Neuroscience·Vivian BudnikFranz Wendler
Jun 30, 2016·The Journal of Cell Biology·Jingyi GongRüdiger Klein
Sep 7, 2016·Current Biology : CB·Aude MarzoPatricia C Salinas

❮ Previous
Next ❯

Citations

Apr 11, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lu WanChunwei Shi
Jan 9, 2020·Frontiers in Neuroscience·Paul M Mathews, Efrat Levy
Sep 30, 2020·Journal of Cell Science·Tamás MatusekPascal P Thérond
Aug 10, 2019·Frontiers in Neuroscience·Ximena CastilloMarietta Zille
Jun 2, 2020·Frontiers in Aging Neuroscience·Yunying Yang, Zhentao Zhang
Nov 26, 2020·International Journal of Molecular Sciences·Morris Losurdo, Mariagrazia Grilli
Oct 19, 2020·Cellular and Molecular Gastroenterology and Hepatology·Chiara LasconiStruan F A Grant
Jun 25, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Juan P CataPatrick M Dougherty
Jul 10, 2021·Frontiers in Cell and Developmental Biology·Yuxuan ZhongJun Fan
Jul 28, 2021·Progress in Neurobiology·Nasim Bahram SanganiChris P Reutelingsperger

❮ Previous
Next ❯

Methods Mentioned

BETA
electron microscopy
density gradient centrifugation
co-immunoprecipitation
transfection
electrophoresis
immunoprecipitation

Software Mentioned

MiniAnalyses
SynPAnal
Excel
pClamp10
GraphPad Prism

Related Concepts

Related Feeds

Brain developing: Influences & Outcomes

This feed focuses on influences that affect the developing brain including genetics, fetal development, prenatal care, and gene-environment interactions. Here is the latest research in this field.