Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage.
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.
Grinspan
J B
JB
Department of Neurology Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. Grinspan@email.chop.edu
Edell
E
E
Carpio
D F
DF
Beesley
J S
JS
Lavy
L
L
Pleasure
D
D
Golden
J A
JA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D018929:Cell Culture Techniques; D019070:Cell Lineage / Q000187:drug effects* / Q000235:genetics; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D005732:Gangliosides / Q000032:analysis / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology; D016212:Transforming Growth Factor beta; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002273:Carcinogens; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D010703:Phorbol Esters; D010982:Platelet-Derived Growth Factor; D013963:Thyroid Hormones; D016212:Transforming Growth Factor beta; C062875:ganglioside A2B5; D016222:Fibroblast Growth Factor 2; D014212:Tretinoin; D003907:Dexamethasone