title: Dual-mode modulation of Smad signaling by Smad-interacting protein Sip1 is required for myelination in the central nervous system.
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.
authors.affiliation: Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Higashi
authors.forename: Veronique
authors.initials: V
authors.lastname: van den Berghe
authors.forename: Eve
authors.initials: E
authors.lastname: Seuntjens
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.forename: Polina
authors.initials: P
authors.lastname: Bukshpun
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D004622:Embryo, Mammalian; D019066:Facies; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009900:Optic Nerve / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D038081:Organogenesis; D012333:RNA, Messenger / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D053148:Caspase 3; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D051785:Smad Proteins; D051906:Smad7 Protein; D000074165:Zinc Finger E-box Binding Homeobox 2; C494786:Olig1 protein, mouse; C512773:Olig2 protein, mouse; C491561:Sip1 protein, mouse; C492363:ZEB2 protein, human