Samanta Jayshree, Kessler John A
Northwestern University's Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, USA.
Development. 2004 Sep;131(17):4131-42. doi: 10.1242/dev.01273. Epub 2004 Jul 27.
Bone morphogenetic protein (BMP) signaling inhibits the generation of oligodendroglia and enhances generation of astrocytes by neural progenitor cells both in vitro and in vivo. This study examined the mechanisms underlying the effects of BMP signaling on glial lineage commitment. Treatment of cultured neural progenitor cells with BMP4 induced expression of all four members of the inhibitor of differentiation (ID) family of helix-loop-helix transcriptional inhibitors and blocked oligodendrocyte (OL) lineage commitment. Overexpression of Id4 or Id2 but not Id1 or Id3 in cultured progenitor cells reproduced both the inhibitory effects of BMP4 treatment on OL lineage commitment and the stimulatory effects on astrogliogenesis. Conversely, decreasing the levels of Id4 mRNA by RNA interference enhanced OL differentiation and inhibited the effects of BMP4 on glial lineage commitment. This suggests that induction of Id4 expression mediates effects of BMP signaling. Bacterial two-hybrid and co-immunoprecipitation studies demonstrated that ID4, and to a lesser extent ID2, complexed with the basic-helix-loop-helix transcription (bHLH) factors OLIG1 and OLIG2, which are required for the generation of OLs. By contrast, ID1 and ID3 did not complex with the OLIG proteins. In addition, the OLIG and ID proteins both interacted with the E2A proteins E12 and E47. Further, exposure of cultured progenitor cells to BMP4 changed the intracellular localization of OLIG1 and OLIG2 from a predominantly nuclear to a predominantly cytoplasmic localization. These observations suggest that the induction of ID4 and ID2, and their sequestration of both OLIG proteins and E2A proteins mediate the inhibitory effects of BMP signaling on OL lineage commitment and contribute to the generation of astrocytes.
骨形态发生蛋白（BMP）信号通路在体外和体内均能抑制少突胶质细胞的生成，并增强神经祖细胞生成星形胶质细胞的能力。本研究探讨了BMP信号通路对神经胶质细胞谱系定向分化作用的潜在机制。用BMP4处理培养的神经祖细胞可诱导螺旋-环-螺旋转录抑制因子分化抑制（ID）家族的所有四个成员的表达，并阻断少突胶质细胞（OL）谱系的定向分化。在培养的祖细胞中过表达Id4或Id2而非Id1或Id3，可重现BMP4处理对OL谱系定向分化的抑制作用以及对星形胶质细胞生成的刺激作用。相反，通过RNA干扰降低Id4 mRNA水平可增强OL分化，并抑制BMP4对神经胶质细胞谱系定向分化的影响。这表明Id4表达的诱导介导了BMP信号通路的作用。细菌双杂交和免疫共沉淀研究表明，ID4以及程度较轻的ID2与OL生成所需的碱性螺旋-环-螺旋转录（bHLH）因子OLIG1和OLIG2形成复合物。相比之下，ID1和ID3不与OLIG蛋白形成复合物。此外，OLIG蛋白和ID蛋白均与E2A蛋白E12和E47相互作用。此外，将培养的祖细胞暴露于BMP4会使OLIG1和OLIG2的细胞内定位从主要位于细胞核变为主要位于细胞质。这些观察结果表明，ID4和ID2的诱导及其对OLIG蛋白和E2A蛋白的隔离介导了BMP信号通路对OL谱系定向分化的抑制作用，并促进了星形胶质细胞的生成。
