title: Mutation of 3-hydroxy-3-methylglutaryl CoA synthase I reveals requirements for isoprenoid and cholesterol synthesis in oligodendrocyte migration arrest, axon wrapping, and myelin gene expression.
abstract: Myelin membrane, which ensheaths axons, has an unusually high amount of cholesterol. Cholesterol influences membrane fluidity and assembles lipid-rich microdomains within membranes, and some studies have shown that cholesterol is important for myelination. How cholesterol influences the development and differentiation of oligodendrocytes, glial cells that make myelin, is not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination. Through a forward genetic screen in zebrafish we discovered that mutation of hmgcs1, which encodes an enzyme necessary for isoprenoid and cholesterol synthesis, causes oligodendrocyte progenitor cells (OPCs) to migrate past their target axons and to fail to express myelin genes. Drawing on a combination of pharmacological inhibitor and rescue experiments, we provide evidence that isoprenoids and protein prenylation, but not cholesterol, are required in OPCs to halt their migration at target axons. On the other hand, cholesterol, but not isoprenoids, is necessary both for axon ensheathment and myelin gene expression. Our data reveal that different products of the cholesterol biosynthetic pathway have distinct roles in oligodendrocyte development and that they together help to coordinate directed migration, axon wrapping, and gene expression.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, and Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Mathews
authors.forename: David J
authors.initials: DJ
authors.lastname: Mawdsley
authors.forename: Macie
authors.initials: M
authors.lastname: Walker
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Hines
authors.forename: Marina
authors.initials: M
authors.lastname: Pozzoli
authors.forename: Bruce
authors.initials: B
authors.lastname: Appel
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D059008:Time-Lapse Imaging; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D006904:Hydroxymethylglutaryl-CoA Synthase
keywords: cholesterol; isoprenoid; myelin; prenylation; zebrafish