Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination. (P2.204)

OBJECTIVE AND BACKGROUND: In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins (Bmp), which form one arm of the transforming growth factor-β family and signal canonically via Smads1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads2/3, 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. DESIGN/METHODS: This work examined transcriptional patterns for Tgfβ superfamily members, their receptors and downstream effectors in developing mouse spinal cord. Studies in vitro tested responses of primary oligodendrocyte cultures and myelinating CNS co-cultures to Tgfβ1, ActB and Bmp4. RESULTS: In mouse neural tube, newly-specified oligodendrocyte progenitors (OLP) 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 whereas 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 strongly 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. CONCLUSIONS: Collectively, these findings suggest that in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation. Disclosure: Dr. Dutta has nothing to disclose. Dr. Zameer has nothing to disclose. Dr. Mariani has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Asp has nothing to disclose. Dr. Huynh has nothing to disclose. Dr. Mahase has nothing to disclose. Dr. Laitman has nothing to disclose. Dr. Tadesse Argaw has nothing to disclose. Dr. Mitiku has nothing to disclose. Dr. Casaccia has nothing to disclose. Dr. Hayot has nothing to disclose. Dr. John has received research support from Teva.