ZFIN ID: ZDB-PUB-140513-462
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
Mathews, E.S., Mawdsley, D.J., Walker, M., Hines, J.H., Pozzoli, M., Appel, B.
Date: 2014
Source: The Journal of neuroscience : the official journal of the Society for Neuroscience   34: 3402-12 (Journal)
Registered Authors: Appel, Bruce, Mawdsley, David, Walker, Macie B.
Keywords: cholesterol, isoprenoid, myelin, prenylation, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Axons/drug effects
  • Axons/metabolism
  • Axons/physiology*
  • Body Patterning/drug effects
  • Body Patterning/genetics
  • Cell Movement/drug effects
  • Cell Movement/genetics*
  • Cell Movement/physiology
  • Cholesterol/metabolism*
  • Embryo, Nonmammalian
  • Enzyme Inhibitors/pharmacology
  • Gene Expression/drug effects
  • Gene Expression/genetics
  • Green Fluorescent Proteins/genetics
  • Hydroxymethylglutaryl-CoA Synthase/genetics*
  • Mutation/genetics*
  • Myelin Sheath/genetics
  • Myelin Sheath/metabolism*
  • Oligodendroglia/drug effects
  • Oligodendroglia/physiology*
  • Spinal Cord/cytology
  • Spinal Cord/embryology
  • Spinal Cord/metabolism
  • Stem Cells/drug effects
  • Stem Cells/physiology
  • Time-Lapse Imaging
  • Zebrafish
  • Zebrafish Proteins/genetics
PubMed: 24573296 Full text @ J. Neurosci.
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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.
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