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 OLPneuron 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.

Activins and Inhibins: Roles in Development, Physiology, and Disease

“…The spinal cords of Inhbb 2/2 embryos display increased apoptosis in the oligodendrocyte lineage and transiently reduced OLP numbers, but cell numbers, maturation, and myelination recover during the first postnatal week. These findings suggest a functional redundancy with other TGF-b family ligands in this process, a contention supported by a more severe and prolonged OLP phenotype in Smad3 2/2 mice (Dutta et al 2014).…”

“…Activin B plays an important developmental role in spinal cord where TGF-b1 and activin B cooperate to support oligodendrocyte development and myelination (Dutta et al 2014). Oligodendrocytes produce myelin, the material that surrounds axons and promotes nerve conduction.…”

“…Cultured oligodendrocyte precursors (OLP) show differential activation of Smad3 and MAPK signaling in response to TGF-b1 and activin B. TGF-b1 increases proliferation while activin B supports maturation. Treatment with both proteins has an additive effect on viability, and enhances proliferation and differentiation, thus increasing the number of mature oligodendrocytes (Dutta et al 2014). The spinal cords of Inhbb 2/2 embryos display increased apoptosis in the oligodendrocyte lineage and transiently reduced OLP numbers, but cell numbers, maturation, and myelination recover during the first postnatal week.…”

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

“…With the many functions of fibrinogen as an OPC differentiation inhibitor with pro-inflammatory and pro-fibrotic functions, anti-coagulant therapies that inhibit fibrin formation or inhibition of fibrinogen binding to immune cell receptors or growth factors might be beneficial for tissue repair. Counteracting inhibitory BMP signaling in OPCs by BMP receptor inhibitors like DMH-1 (our study) or pro-myelinating ligands like activin B (Dutta et al, 2014) may alleviate the inhibitory effects of fibrinogen on remyelination. Novel inhibitors may overcome the hostile, dysregulated environment that persists in chronically demyelinated lesions and open new therapeutic strategies to promote regeneration in neurological diseases with fibrin deposition.…”

Comparative analysis of activins A and B in the adult mouse epididymis and vas deferens

“…For example, while both activin A and B regulate embryonic mesoderm induction, activin B is more potent (Sokol et al 1991, Nakamura et al 1992). Furthermore, activin B plays a more important role in embryonic development of the central nervous system (Dutta et al 2014, Feijen et al 1994). On the other hand, activin A appears to be a more effective regulator of testicular development compared to activin B, because Inhba BK/BK mice, in which activin A has been replaced by an activin B-producing transgene, show a delay in testicular development (Brown et al 2000) and altered postnatal germ cell maturation (Mithraprabhu et al 2010).…”