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Notably, EVs have been found and characterized in the male reproductive tract, however, direct functional evidence for their importance in mediating sperm function is lacking. We have previously demonstrated that Arrdc4, a member of the \u03b1\u2010arrestin protein family, is involved in extracellular vesicle biogenesis and release. Here we show that Arrdc4\u2010mediated extracellular vesicle biogenesis is required for proper sperm function. Sperm from <jats:italic>Arrdc4<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice develop normally through the testis but fail to acquire adequate motility and fertilization capabilities through the epididymis, as observed by reduced motility, premature acrosome reaction, reduction in zona pellucida binding and two\u2010cell embryo production. We found a significant reduction in extracellular vesicle production by <jats:italic>Arrdc4<jats:sup>\u2013\/\u2010<\/jats:sup><\/jats:italic> epididymal epithelial cells, and further, supplementation of <jats:italic>Arrdc4<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> sperm with additional vesicles dampened the acrosome reaction defect and restored zona pellucida binding. These results indicate that Arrdc4 is important for proper sperm maturation through the control of extracellular vesicle biogenesis.<\/jats:p>","DOI":"10.1002\/jev2.12113","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T04:12:01Z","timestamp":1624335121000},"source":"Crossref","is-referenced-by-count":26,"title":["Arrdc4\u2010dependent extracellular vesicle biogenesis is required for sperm maturation"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6567-9283","authenticated-orcid":false,"given":"Natalie J.","family":"Foot","sequence":"first","affiliation":[{"name":"Centre for Cancer Biology University of South Australia and SA Pathology  Adelaide South Australia Australia"},{"name":"School of Medicine Robinson Research Institute University of Adelaide  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macarena 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