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However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes including amyloid precursor protein (APP), synaptotagmin-4 (Syt4), and neuroglian (Nrg) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer. Conversely, mutations in rab11 and rab4, regulators of endosome-plasma membrane recycling, cause reduced EV cargo levels, and rab11 suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab4\/Rab11 recycling and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer\u2019s disease, and suggest that misregulated EV traffic may be an underlying defect.<\/jats:p>","DOI":"10.1083\/jcb.202012034","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T02:22:12Z","timestamp":1619749332000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Opposing functions for retromer and Rab11 in extracellular vesicle traffic at presynaptic terminals"],"prefix":"10.1083","volume":"220","author":[{"given":"Rylie B.","family":"Walsh","sequence":"first","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica C.","family":"Dresselhaus","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata N.","family":"Becalska","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6281-8284","authenticated-orcid":true,"given":"Matthew J.","family":"Zunitch","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra R.","family":"Blanchette","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7560-275X","authenticated-orcid":true,"given":"Amy L.","family":"Scalera","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6710-7676","authenticated-orcid":true,"given":"Tania","family":"Lemos","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4493-9306","authenticated-orcid":true,"given":"Julia","family":"Apiki","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-6319","authenticated-orcid":true,"given":"ShiYu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berith","family":"Isaac","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9670-1252","authenticated-orcid":true,"given":"Anna","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Koles","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2051-8304","authenticated-orcid":true,"given":"Avital A.","family":"Rodal","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"2023072823310241600_bib1","doi-asserted-by":"publisher","first-page":"3425","DOI":"10.1523\/JNEUROSCI.2752-16.2017","article-title":"Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments","volume":"37","author":"Akbergenova","year":"2017","journal-title":"J. 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