| Authors |
Dutta DJ, Zameer A, Mariani JN, Zhang J, Asp L, Huynh J, Mahase S, Laitman BM,
Argaw AT, Mitiku N, Urbanski M, Melendez-Vasquez CV, Casaccia P, Hayot F,
Bottinger EP, Brown CW, John GR
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| Submitted By |
Submitted Externally on 8/5/2014 |
| Status |
Published |
| Journal |
Development (Cambridge, England) |
| Year |
2014 |
| Date Published |
6/1/2014 |
| Volume : Pages |
141 : 2414 - 2428 |
| PubMed Reference |
|
| 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-脽 (Tgf脽) family and signal canonically via Smads 1/5/8. Tgf脽
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 Tgf脽 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 Tgf脽 ligands in isolation, then later in combination with ActB during
maturation. In primary OLP cultures, Tgf脽1 and ActB differentially activate
canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance
viability, and Tgf脽1 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, Tgf脽 ligands and ActB together support
oligodendrocyte development and myelin formation.
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