title: Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.
abstract: In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLP-neuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb(-/-) embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3(-/-) mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Dipankar J
authors.initials: DJ
authors.lastname: Dutta
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Andleeb
authors.initials: A
authors.lastname: Zameer
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Mariani
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Linnea
authors.initials: L
authors.lastname: Asp
authors.affiliation: Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Mahase
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Laitman
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Azeb Tadesse
authors.initials: AT
authors.lastname: Argaw
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Nesanet
authors.initials: N
authors.lastname: Mitiku
authors.affiliation: Biological Sciences, Hunter College, New York, NY 10065, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Urbanski
authors.affiliation: Biological Sciences, Hunter College, New York, NY 10065, USA.
authors.forename: Carmen V
authors.initials: CV
authors.lastname: Melendez-Vasquez
authors.affiliation: Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA Systems Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Fernand
authors.initials: F
authors.lastname: Hayot
authors.affiliation: Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA Charles Bronfman Institute for Personalized Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
authors.affiliation: Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chester W
authors.initials: CW
authors.lastname: Brown
authors.affiliation: Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY 10029, USA Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA gareth.john@mssm.edu.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: John
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology*; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics; D013116:Spinal Cord / Q000196:embryology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D008024:Ligands; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C044147:activin B; D028341:Activins
keywords: Activin; Myelin; Oligodendrocyte; Smad; Transforming growth factor