Wu Yuanyuan, Liu Ying, Levine Edward M, Rao Mahendra S
Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Dev Dyn. 2003 Apr;226(4):675-89. doi: 10.1002/dvdy.10278.
To determine the role of Hes genes in the differentiation process of neuroepithelial (NEP) cells to glial restricted precursor cells (GRPs) and subsequently GRPs to oligodendrocytes and astrocytes, we have examined the effects of Hes1 and Hes5 on glial differentiation. We find that both Hes1 and Hes5 are expressed by GRPs and that Hes1 can drive GRPs to an astrocyte cell fate at the expense of oligodendrocyte differentiation. Overexpression of Hes1 in GRPs results in the up-regulation of the astrocyte markers glial fibrillary acidic protein and CD44 and the down-regulation of oligodendrocyte markers myelin proteolipid protein/DM20, GalC, and CNPase. Transcription factors involved in oligodendrocyte differentiation, such as Nkx2.2, Olig1, and Mash1, are also down-regulated in Hes1-overexpressing cells. The effect of Hes1 on gliogenesis is stage-specific as Hes1 does not direct NEP cells to an astrocytic fate. In contrast to Hes1, Hes5 does not promote astrocyte differentiation. Instead, it inhibits both astrocyte and oligodendrocyte differentiation. Overexpression of Notch1 has an effect on gliogenesis similar to that of Hes1 and the mRNA levels of Hes1 are up-regulated in cells overexpressing Notch1, suggesting that Notch1 could be an upstream activator of Hes1.
为了确定Hes基因在神经上皮（NEP）细胞向神经胶质限制前体细胞（GRP）分化过程中，以及随后GRP向少突胶质细胞和星形胶质细胞分化过程中的作用，我们研究了Hes1和Hes5对神经胶质分化的影响。我们发现Hes1和Hes5均由GRP表达，并且Hes1能够促使GRP向星形胶质细胞命运分化，同时以少突胶质细胞分化为代价。在GRP中过表达Hes1会导致星形胶质细胞标志物胶质纤维酸性蛋白和CD44上调，以及少突胶质细胞标志物髓鞘蛋白脂蛋白/DM20、半乳糖脑苷脂（GalC）和2',3'-环核苷酸3'-磷酸二酯酶（CNPase）下调。参与少突胶质细胞分化的转录因子，如Nkx2.2、Olig1和Mash1，在过表达Hes1的细胞中也下调。Hes1对神经胶质生成的影响具有阶段特异性，因为Hes1不会将NEP细胞导向星形胶质细胞命运。与Hes1相反，Hes5不促进星形胶质细胞分化。相反，它抑制星形胶质细胞和少突胶质细胞的分化。Notch1过表达对神经胶质生成的影响与Hes1相似，并且在过表达Notch1的细胞中Hes1的mRNA水平上调，这表明Notch1可能是Hes仁的上游激活因子。
