Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System
Copyright policy )Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System
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.
- Columbia University United States
- The University of Texas Southwestern Medical Center United States
- Université Catholique de Louvain Belgium
- Zhejiang University
- Katholieke Universiteit Leuven Belgium
Models, Molecular, Central Nervous System, Receptor, Platelet-Derived Growth Factor alpha, Organogenesis, 1702 Cognitive Sciences, Smad Proteins, BETA-CATENIN, Mice, Basic Helix-Loop-Helix Transcription Factors, Myelin Sheath, Cells, Cultured, Oligonucleotide Array Sequence Analysis, OLIGODENDROCYTE PRECURSOR CELLS, Mice, Knockout, BONE MORPHOGENETIC PROTEIN, Caspase 3, CNS MYELINATION, MOWAT-WILSON-SYNDROME, Age Factors, Gene Expression Regulation, Developmental, Cell Differentiation, MULTIPLE-SCLEROSIS, Oligodendroglia, TRANSCRIPTION FACTORS, DIFFERENTIATION, Receptor-Interacting Protein Serine-Threonine Kinases, Bone Morphogenetic Proteins, Microcephaly, DEMYELINATED LESIONS, Life Sciences & Biomedicine, Signal Transduction, Neuroscience(all), Green Fluorescent Proteins, Nerve Tissue Proteins, Transfection, Smad7 Protein, Microscopy, Electron, Transmission, Intellectual Disability, Animals, Humans, Immunoprecipitation, RNA, Messenger, Hirschsprung Disease, Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Science & Technology, Neurology & Neurosurgery, Gene Expression Profiling, Neurosciences, Facies, Optic Nerve, IN-VITRO, Oligodendrocyte Transcription Factor 2, Embryo, Mammalian, Repressor Proteins, Ki-67 Antigen, Animals, Newborn, 1701 Psychology, 5202 Biological psychology, 3209 Neurosciences, Neurosciences & Neurology, 1109 Neurosciences
Models, Molecular, Central Nervous System, Receptor, Platelet-Derived Growth Factor alpha, Organogenesis, 1702 Cognitive Sciences, Smad Proteins, BETA-CATENIN, Mice, Basic Helix-Loop-Helix Transcription Factors, Myelin Sheath, Cells, Cultured, Oligonucleotide Array Sequence Analysis, OLIGODENDROCYTE PRECURSOR CELLS, Mice, Knockout, BONE MORPHOGENETIC PROTEIN, Caspase 3, CNS MYELINATION, MOWAT-WILSON-SYNDROME, Age Factors, Gene Expression Regulation, Developmental, Cell Differentiation, MULTIPLE-SCLEROSIS, Oligodendroglia, TRANSCRIPTION FACTORS, DIFFERENTIATION, Receptor-Interacting Protein Serine-Threonine Kinases, Bone Morphogenetic Proteins, Microcephaly, DEMYELINATED LESIONS, Life Sciences & Biomedicine, Signal Transduction, Neuroscience(all), Green Fluorescent Proteins, Nerve Tissue Proteins, Transfection, Smad7 Protein, Microscopy, Electron, Transmission, Intellectual Disability, Animals, Humans, Immunoprecipitation, RNA, Messenger, Hirschsprung Disease, Zinc Finger E-box Binding Homeobox 2, Homeodomain Proteins, Science & Technology, Neurology & Neurosurgery, Gene Expression Profiling, Neurosciences, Facies, Optic Nerve, IN-VITRO, Oligodendrocyte Transcription Factor 2, Embryo, Mammalian, Repressor Proteins, Ki-67 Antigen, Animals, Newborn, 1701 Psychology, 5202 Biological psychology, 3209 Neurosciences, Neurosciences & Neurology, 1109 Neurosciences
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