Sphingolipid-dependent Dscam sorting regulates axon segregation

Gaurav Goyal (), Junfeng Zheng, Elisabeth Adam, Georg Steffes, Mamta Jain, Kristaps Klavins and Thomas Hummel ()
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Gaurav Goyal: University of Vienna
Junfeng Zheng: Universität Münster
Elisabeth Adam: University of Vienna
Georg Steffes: Universität Münster
Mamta Jain: Medical University of Vienna
Kristaps Klavins: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Thomas Hummel: University of Vienna

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Neurons are highly polarized cells with distinct protein compositions in axonal and dendritic compartments. 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 Drosophila brain circuit development, we identified mutations in SPT, an evolutionary conserved enzyme in sphingolipid biosynthesis. Here we show that reduced levels of sphingolipids in SPT 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, SPT mutations causing neurodegenerative HSAN-I disorder in humans also result in formation of stable Dscam aggregates and axonal branch phenotypes in Drosophila neurons, indicating a causal link between developmental protein sorting defects and neuronal dysfunction.

Date: 2019
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DOI: 10.1038/s41467-019-08765-2

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