Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage

Abstract

Oligodendrocyte maturation is regulated by multiple secreted factors present in the brain during critical stages of development. Whereas most of these factors promote oligodendrocyte proliferation and survival, members of the bone morphogenetic protein family (BMPs) recently have been shown to inhibit oligodendrocyte differentiation in vitro. Oligodendrocyte precursors treated with BMPs differentiate to the astrocyte lineage. Given that cells at various stages of the oligodendrocyte lineage have distinct responses to growth factors, we hypothesized that the response to BMP would be stage‐specific. Using highly purified, stage‐specific cultures, we found that BMP has distinct effects on cultured oligodendrocyte preprogenitors, precursors, and mature oligodendrocytes. Oligodendrocyte preprogenitors (PSA‐NCAM+, A2B5−) treated with BMP2 or BMP4 developed a novel astrocyte phenotype characterized by a morphological change and expression of glial fibrillary acidic protein (GFAP) but little glutamine synthetase expression and no labeling with A2B5 antibody. In contrast, treating oligodendrocyte precursors with BMPs resulted in the accumulation of cells with the traditional type 2 astrocyte phenotype (GFAP+, A2B5+). However, many of the cells with an astrocytic morphology did not express GFAP or glutamine synthetase unless thyroid hormone was present in the medium. The addition of fibroblast growth factor along with BMP to either oligodendrocyte preprogenitor or the oligodendrocyte precursor cells inhibited the switch to the astrocyte lineage, whereas platelet‐derived growth factor addition had no effect. Treatment of mature oligodendrocytes with BMP elicited no change in morphology or expression of GFAP. These data suggest that as cells progress through the oligodendrocyte lineage, they show developmentally restricted responses to the BMPs. © 2000 John Wiley & Sons, Inc. J Neurobiol 43: 1–17, 2000

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

“…Moreover, cell-extrinsic signaling molecules (e.g., neurotrophin-3 [NT-3] and fibroblast growth factor-2 [FGF-2]) that enhance the self-renewal of progenitors dividing in response to PDGF cause cells to become more reduced. In contrast, signaling molecules that induce differentiation to oligodendrocytes (i.e., thyroid hormone [TH] [63,64]) or astrocytes (i.e., bone morphogenetic protein-4 [BMP-4] [65,66]) cause cells to become more oxidized [59]. The ability of these signaling molecules to alter redox state is essential to their mechanisms of action, because pharmacological inhibition of the redox changes they induce blocks their effects on either division or differentiation of O-2A/OPCs.…”

Glial Development: The Crossroads of Regeneration and Repair in the CNS

“…Among key pathways implicated in GFAP regulation, CNTF/LIF/CT-1 cytokine signaling through gp130 and JAK/STAT has been shown in several developmental models to be a key regulator of GFAP and astrocyte differentiation as a whole (Barnabe-Heider et al, 2005; Bonni et al, 1997; Miller and Gauthier, 2007; Sun et al, 2001). Additionally, Notch- and BMP-signaling have been implicated in regulating GFAP-expression and some aspects of astrocyte development, including inhibition of alternative cell fates (Bonaguidi et al, 2005; Grinspan et al, 2000; Namihira et al, 2009; Taylor et al, 2007). Newborn neurons are thought to be the source of these signaling molecules, as separate studies have suggested that CT-1 and Jagged/delta released from neurons promote astrocyte differentiation in vitro (Barnabe-Heider et al, 2005; Namihira et al, 2009).…”

Remyelinating strategies in multiple sclerosis

“…OPC and oligodendrocytes derived from the CNS show expression of BMP4 and BMP receptors [171]. Exogenous BMP4 inhibits OPC differentiation and promotes astroglial differentiation [172,173]. Recently, it has been shown that BMP signaling is active in demyelinating lesions in mice [174].…”