title: Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling.
abstract: Receptor tyrosine kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling. Drosophila has a simple GSL biosynthetic pathway, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what extent this effect involves changes in upstream signaling events is unresolved. We show here that glial overgrowth in egh is strongly linked to increased activation of Insulin and fibroblast growth factor receptors (FGFR). Glial hypertrophy is phenocopied when overexpressing gain-of-function mutants of the Drosophila insulin receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of insulin and fibroblast growth factor receptors in Drosophila glia.
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.|Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Gerdøe-Kristensen
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Viktor K
authors.initials: VK
authors.lastname: Lund
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Wandall
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Ole
authors.identifier: http://orcid.org/0000-0002-8654-1435
authors.initials: O
authors.lastname: Kjaerulff
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D049108:Cell Enlargement; D002518:Ceramides / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006984:Hypertrophy; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002518:Ceramides; D029721:Drosophila Proteins; D008024:Ligands; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C103963:brn protein, Drosophila; C103962:egh protein, Drosophila; C106354:flotillins; D005700:Galactosyltransferases; C023235:glucosylceramide beta-1-4-galactosyltransferase; C094982:InR protein, Drosophila; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C102667:htl protein, Drosophila
keywords: cell growth; glia; glioblastoma; sphingolipids