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Cellular mechanisms controlling polarized protein sorting have been described for mature nervous system but little is known about the segregation in newly differentiated neurons. In a forward genetic screen for regulators of <jats:italic>Drosophila<\/jats:italic> brain circuit development, we identified mutations in SPT, an evolutionary conserved enzyme in sphingolipid biosynthesis. Here we show that reduced levels of sphingolipids in <jats:italic>SPT<\/jats:italic> mutants cause axonal morphology defects similar to loss of cell recognition molecule Dscam. Loss- and gain-of-function studies show that neuronal sphingolipids are critical to prevent aggregation of axonal and dendritic Dscam isoforms, thereby ensuring precise Dscam localization to support axon branch segregation. Furthermore, <jats:italic>SPT<\/jats:italic> mutations causing neurodegenerative HSAN-I disorder in humans also result in formation of stable Dscam aggregates and axonal branch phenotypes in <jats:italic>Drosophila<\/jats:italic> neurons, indicating a causal link between developmental protein sorting defects and neuronal dysfunction.<\/jats:p>","DOI":"10.1038\/s41467-019-08765-2","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T11:03:22Z","timestamp":1550487802000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Sphingolipid-dependent Dscam sorting regulates axon segregation"],"prefix":"10.1038","volume":"10","author":[{"given":"Gaurav","family":"Goyal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junfeng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Adam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Steffes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamta","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristaps","family":"Klavins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hummel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,2,18]]},"reference":[{"key":"8765_CR1","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/nrn2852","volume":"11","author":"MN Rasband","year":"2010","unstructured":"Rasband, M. 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