Abstract
Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/β-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and β-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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Animals, Newborn
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Bone Morphogenetic Proteins / metabolism
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Caspase 3 / metabolism
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Cell Differentiation / genetics
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Cells, Cultured
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Central Nervous System / cytology
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Central Nervous System / physiology*
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Central Nervous System / ultrastructure
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Embryo, Mammalian
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Facies
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Gene Expression Profiling
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Gene Expression Regulation, Developmental / genetics*
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Green Fluorescent Proteins / genetics
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Hirschsprung Disease / genetics
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Hirschsprung Disease / pathology
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Homeodomain Proteins / metabolism
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Humans
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Immunoprecipitation
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Intellectual Disability / genetics
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Intellectual Disability / pathology
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Ki-67 Antigen / metabolism
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Mice
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Mice, Knockout
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Microcephaly / genetics
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Microcephaly / pathology
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Microscopy, Electron, Transmission
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Models, Molecular
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Myelin Sheath / metabolism*
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Oligodendrocyte Transcription Factor 2
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Oligodendroglia / metabolism
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Oligonucleotide Array Sequence Analysis
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Optic Nerve / embryology
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Optic Nerve / growth & development
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Optic Nerve / metabolism
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Organogenesis
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RNA, Messenger / metabolism
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Smad Proteins / genetics
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Smad Proteins / metabolism*
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Smad7 Protein / genetics
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Smad7 Protein / metabolism
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Transfection
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Zinc Finger E-box Binding Homeobox 2
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Bone Morphogenetic Proteins
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Homeodomain Proteins
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Ki-67 Antigen
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Nerve Tissue Proteins
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Olig1 protein, mouse
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Olig2 protein, mouse
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Oligodendrocyte Transcription Factor 2
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RNA, Messenger
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Repressor Proteins
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Sip1 protein, mouse
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Smad Proteins
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Smad7 Protein
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ZEB2 protein, human
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Zinc Finger E-box Binding Homeobox 2
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Green Fluorescent Proteins
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Receptor, Platelet-Derived Growth Factor alpha
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Receptor-Interacting Protein Serine-Threonine Kinases
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Caspase 3
Associated data
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GEO/GSE40431
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GEO/GSE40506
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GEO/GSE40510