Torii M a, Matsuzaki F, Osumi N, Kaibuchi K, Nakamura S, Casarosa S, Guillemot F, Nakafuku M
Division of Neurobiology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-0033 Japan.
Development. 1999 Feb;126(3):443-56. doi: 10.1242/dev.126.3.443.
Like other tissues and organs in vertebrates, multipotential stem cells serve as the origin of diverse cell types during genesis of the mammalian central nervous system (CNS). During early development, stem cells self-renew and increase their total cell numbers without overt differentiation. At later stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step in cell differentiation remain poorly understood. In this study, we present evidence that the expression and function of the neural-specific transcription factors Mash-1 and Prox-1 are involved in this process. In vivo, Mash-1- and Prox-1-expressing cells were defined as a transient proliferating population that was molecularly distinct from self-renewing stem cells. By taking advantage of in vitro culture systems, we showed that induction of Mash-1 and Prox-1 coincided with an initial step of differentiation of stem cells. Furthermore, forced expression of Mash-1 led to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and up-regulation of Prox-1, suggesting that Mash-1 positively regulates cell differentiation. In support of these observations in vitro, we found specific defects in cellular differentiation and loss of expression of Prox-1 in the developing brain of Mash-1 mutant mice in vivo. Thus, we propose that induction of Mash-1 and Prox-1 is one of the critical molecular events that control early development of the CNS.
与脊椎动物的其他组织和器官一样，多能干细胞是哺乳动物中枢神经系统（CNS）发育过程中多种细胞类型的起源。在早期发育过程中，干细胞自我更新并增加其总细胞数量，而无明显分化。在后期阶段，细胞退出这种自我更新模式，并注定以空间和时间调控的方式分化为神经元和神经胶质细胞。然而，细胞分化这一重要步骤背后的分子机制仍知之甚少。在本研究中，我们提供证据表明神经特异性转录因子Mash-1和Prox-1的表达及功能参与了这一过程。在体内，表达Mash-1和Prox-1的细胞被定义为一个短暂增殖群体，在分子水平上与自我更新的干细胞不同。通过利用体外培养系统，我们表明Mash-1和Prox-1的诱导与干细胞分化的初始步骤相吻合。此外，Mash-1的强制表达导致未分化神经上皮细胞标志物巢蛋白的下调以及Prox-1的上调，表明Mash-1正向调节细胞分化。为支持体外的这些观察结果，我们在体内发现Mash-1突变小鼠发育中的大脑存在细胞分化的特定缺陷以及Prox-1表达缺失。因此，我们提出Mash-1和Prox-1的诱导是控制中枢神经系统早期发育的关键分子事件之一。
