Oligodendroglial myelination requires astrocyte-derived lipids

• Published in: PLoS biology Vol. 15; no. 5; p. e1002605
• Main Authors: Camargo, Nutabi, Goudriaan, Andrea, van Deijk, Anne-Lieke F, Otte, Willem M, Brouwers, Jos F, Lodder, Hans, Gutmann, David H, Nave, Klaus-Armin, Dijkhuizen, Rick M, Mansvelder, Huibert D, Chrast, Roman, Smit, August B, Verheijen, Mark H G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2017; Public Library of Science (PLoS)
• Subjects: Age; Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Astrocytes - ultrastructure; Axons; Biology and Life Sciences; Biomarkers - metabolism; Biosynthesis; Brain; Brain research; Central nervous system; Cleavage; Clonal deletion; Crosses, Genetic; Deactivation; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Demyelinating Diseases - prevention & control; Developmental biology; Diet, High-Fat; Embryos; Enrichment; Fatty Acid Synthase, Type I - metabolism; Fluctuations; Flux; Gene Deletion; Glial cells; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Humans; Inactivation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipid Metabolism; Lipids; Medicin och hälsovetenskap; Medicine and Health Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Mutants; Mutation; Myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Myelination; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system; Neurobiology; Neurons; Oligodendrocytes; Oligodendroglia - metabolism; Oligodendroglia - pathology; Oligodendroglia - ultrastructure; Organ Specificity; Physical Sciences; Propagation; Protein Processing, Post-Translational; Proteins; Schwann cells; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; Sterol regulatory element-binding protein; Netherlands
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002605

In the vertebrate nervous system, myelination of axons for rapid impulse propagation requires the synthesis of large amounts of lipids and proteins by oligodendrocytes and Schwann cells. Myelin membranes are thought to be cell-autonomously assembled by these axon-associated glial cells. Here, we report the surprising finding that in normal brain development, a substantial fraction of the lipids incorporated into central nervous system (CNS) myelin are contributed by astrocytes. The oligodendrocyte-specific inactivation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), an essential coactivator of the transcription factor SREBP and thus of lipid biosynthesis, resulted in significantly retarded CNS myelination; however, myelin appeared normal at 3 months of age. Importantly, embryonic deletion of the same gene in astrocytes, or in astrocytes and oligodendrocytes, caused a persistent hypomyelination, as did deletion from astrocytes during postnatal development. Moreover, when astroglial lipid synthesis was inhibited, oligodendrocytes began incorporating circulating lipids into myelin membranes. Indeed, a lipid-enriched diet was sufficient to rescue hypomyelination in these conditional mouse mutants. We conclude that lipid synthesis by oligodendrocytes is heavily supplemented by astrocytes in vivo and that horizontal lipid flux is a major feature of normal brain development and myelination.