ASCL1调节胚胎和成人脊髓中NG2胶质细胞的增殖
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摘要
NG2胶质细胞是高度增殖的少突胶质细胞的前体细胞(OPCs),广泛分布于整个中枢神经系统(CNS)。在发育过程中,NG2-glia主要分化为少突胶质细胞(OL)迁移至髓鞘轴突纤维,但它们也可作为OPCs保留在成熟的CNS中。有趣的是,灰质(GM)中的NG2胶质细胞在增殖、分化、基因表达和电生理学特性方面与白质(WM)中的NG2胶质细胞有着本质上的不同。本文研究转录调节因子ASCL1在控制GM和WM中NG2胶质细胞分布和发育中的作用。在脊髓中,WM的NG2胶质细胞中ASCL1水平高于GM中的水平。WM和GM的NG2胶质细胞中ASCL1的这种差异水平维持到成人阶段。长期克隆谱系分析显示,即使它们经历广泛增殖以在脊髓中产生大的OLs簇,单个ASCL1+少突胶质细胞祖细胞(OLP)和NG2胶质细胞的后代仍主要限于GM或WM。特异性地在胚胎或成年脊髓中的NG2胶质细胞中条件性删除Asc1导致这些细胞的增殖显著减少,并非分化减少。这些发现表明,ASCL1是CNS中NG2胶质细胞增殖特性的内在调节因子。
NG2-glia are highly proliferative oligodendrocyte precursor cells(OPCs) that are widely distributed throughout the central nervous system(CNS). During development, NG2-glia predominantly differentiate into oligodendrocytes(OLs) to myelinate axon fibers, but they can also remain as OPCs persisting into the mature CNS. Interestingly, NG2-glia in the gray matter(GM) are intrinsically different from those in the white matter(WM) in terms of proliferation, differentiation, gene expression, and electrophysiological properties. Here we investigate the role of the transcriptional regulator, ASCL1, in controlling NG2-glia distribution and development in the GM and WM. In the spinal cord, ASCL1 levels are higher in WM NG2-glia than those in the GM. This differential level of ASCL1 in WM and GM NG2-glia is maintained into adult stages. Long-term clonal lineage analysis reveals that the progeny of single ASCL1+oligodendrocyte progenitors(OLPs) and NG2-glia are primarily restricted to the GM or WM, even though they undergo extensive proliferation to give rise to large clusters of OLs in the postnatal spinal cord. Conditional deletion of Ascl1 specifically in NG2-glia in the embryonic or adult spinal cord resulted in a significant reduction in the proliferation but not differentiation of these cells. These findings illustrate that ASCL1 is an intrinsic regulator of the proliferative property of NG2-glia in the CNS.
NG2-glia are highly proliferative oligodendrocyte precursor cells(OPCs) that are widely distributed throughout the central nervous system(CNS). During development, NG2-glia predominantly differentiate into oligodendrocytes(OLs) to myelinate axon fibers, but they can also remain as OPCs persisting into the mature CNS. Interestingly, NG2-glia in the gray matter(GM) are intrinsically different from those in the white matter(WM) in terms of proliferation, differentiation, gene expression, and electrophysiological properties. Here we investigate the role of the transcriptional regulator, ASCL1, in controlling NG2-glia distribution and development in the GM and WM. In the spinal cord, ASCL1 levels are higher in WM NG2-glia than those in the GM. This differential level of ASCL1 in WM and GM NG2-glia is maintained into adult stages. Long-term clonal lineage analysis reveals that the progeny of single ASCL1+oligodendrocyte progenitors(OLPs) and NG2-glia are primarily restricted to the GM or WM, even though they undergo extensive proliferation to give rise to large clusters of OLs in the postnatal spinal cord. Conditional deletion of Ascl1 specifically in NG2-glia in the embryonic or adult spinal cord resulted in a significant reduction in the proliferation but not differentiation of these cells. These findings illustrate that ASCL1 is an intrinsic regulator of the proliferative property of NG2-glia in the CNS.
引文