Bani-Yaghoub Mahmud, Tremblay Roger G, Lei Joy X, Zhang Dongling, Zurakowski Bogdan, Sandhu Jagdeep K, Smith Brandon, Ribecco-Lutkiewicz Maria, Kennedy Jessica, Walker P Roy, Sikorska Marianna
Neurogenesis and Brain Repair Group, Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Rd., Bldg. M-54, Ottawa, ON, Canada K1A 0R6.
Dev Biol. 2006 Jul 1;295(1):52-66. doi: 10.1016/j.ydbio.2006.03.007. Epub 2006 Apr 24.
The mammalian neocortex is established from neural stem and progenitor cells that utilize specific transcriptional and environmental factors to create functional neurons and astrocytes. Here, we examined the mechanism of Sox2 action during neocortical neurogenesis and gliogenesis. We established a robust Sox2 expression in neural stem and progenitor cells within the ventricular zone, which persisted until the cells exited the cell cycle. Overexpression of constitutively active Sox2 in neural progenitors resulted in upregulation of Notch1, recombination signal-sequence binding protein-J (RBP-J) and hairy enhancer of split 5 (Hes5) transcripts and the Sox2 high mobility group (HMG) domain seemed sufficient to confer these effects. While Sox2 overexpression permitted the differentiation of progenitors into astroglia, it inhibited neurogenesis, unless the Notch pathway was blocked. Moreover, neuronal precursors engaged a serine protease(s) to eliminate the overexpressed Sox2 protein and relieve the repression of neurogenesis. Glial precursors and differentiated astrocytes, on the other hand, maintained Sox2 expression until they reached a quiescent state. Sox2 expression was re-activated by signals that triggered astrocytic proliferation (i.e., injury, mitogenic and gliogenic factors). Taken together, Sox2 appears to act upstream of the Notch signaling pathway to maintain the cell proliferative potential and to ensure the generation of sufficient cell numbers and phenotypes in the developing neocortex.
哺乳动物新皮层由神经干细胞和祖细胞形成，这些细胞利用特定的转录和环境因子来产生功能性神经元和星形胶质细胞。在此，我们研究了Sox2在新皮层神经发生和胶质发生过程中的作用机制。我们在脑室区的神经干细胞和祖细胞中建立了强大的Sox2表达，这种表达一直持续到细胞退出细胞周期。在神经祖细胞中组成型激活的Sox2过表达导致Notch1、重组信号序列结合蛋白-J（RBP-J）和分裂增强子5（Hes5）转录本上调，并且Sox2高迁移率族（HMG）结构域似乎足以赋予这些效应。虽然Sox2过表达允许祖细胞分化为星形胶质细胞，但它抑制神经发生，除非Notch信号通路被阻断。此外，神经元前体利用一种丝氨酸蛋白酶来消除过表达的Sox2蛋白并解除对神经发生的抑制。另一方面，胶质前体和分化的星形胶质细胞维持Sox2表达，直到它们达到静止状态。Sox2表达被触发星形胶质细胞增殖的信号（即损伤、促有丝分裂和促胶质生成因子）重新激活。综上所述，Sox2似乎在Notch信号通路的上游起作用，以维持细胞增殖潜能，并确保在发育中的新皮层中产生足够数量的细胞和细胞表型。
