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Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells

机译：依赖Tbx6的Sox2调控决定轴向干细胞的神经或中胚层命运

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摘要

The classical view of neural plate development held that it arises from the ectoderm, after its separation from the mesodermal and endodermal lineages. However, recent cell-lineage-tracing experiments indicate that the caudal neural plate and paraxial mesoderm are generated from common bipotential axial stem cells originating from the caudal lateral epiblast. Tbx6null mutant mouse embryos which produce ectopic neural tubes at the expense of paraxial mesoderm must provide a clue to the regulatory mechanism underlying this neural versus mesodermal fate choice. Here we demonstrate that Tbx6-dependent regulation of Sox2 determines the fate of axial stem cells. In wild-type embryos, enhancer Nl of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain Nl activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer Nl before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer Nl activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-Nl-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation in the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer Nl. Tbx6-dependent repression of Wnt3a in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wild-type embryos resulted in ectopic neural tube development. Thus, Tbx6 represses Sox2 by inactivating enhancer Nl to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.
机译：神经板发育的经典观点认为，它是由外胚层与中胚层和内胚层谱系分离后产生的。但是，最近的细胞谱系追踪实验表明，尾神经板和近轴中胚层是由源自尾外侧上皮细胞的常见双能轴向干细胞产生的。 Tbx6null突变小鼠胚胎以异轴中胚层为代价产生异位神经管，必须为这种神经对中胚层命运选择提供调控机制的线索。在这里，我们证明了Sox2依赖Tbx6的调控决定了轴向干细胞的命运。在野生型胚胎中，神经原始基因Sox2的增强子N1在尾侧上皮细胞中被激活，并且停留在表层的细胞维持N1活性并激活神经板中的Sox2表达。相反，注定要变成中胚层的细胞在迁移到近轴中胚层隔室之前激活Tbx6并关闭增强子N1。然而，在Tbx6突变体胚胎中，增强子N1活性在近轴中胚层隔室中持续存在，引起异位Sox2激活并将近轴中胚层转化为神经管。引入Tbx6突变体胚胎中的增强子-N1特异性缺失突变阻止了中胚层隔室中的该Sox2活化和异位神经管的随后发育，表明Tbx6通过增强子N1调节Sox2。 Tbx6依赖Wnt3a抑制近轴中胚层隔室参与此调控过程。在野生型胚胎中Sox2转基因的近轴中胚层特异性错误表达导致异位神经管发育。因此，Tbx6通过使增强子N1失活以抑制神经发育来抑制Sox2，这是从轴向干细胞确定近轴中胚层的必不可少的步骤。

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  • 来源
    《Nature》 |2011年第7334期|p.394-398|共5页
  • 作者

    Tatsuya Takemoto; Masanori Uchikawa; Megumi Yoshida; Donald M. Bell; Robin Lovell-Badge; Virginia E. Papaioannou; Hisato Kondoh;

  • 作者单位

    Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan;

    rnDivision of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research.TheRidgeway, Mill Hill, London NW7 1AA, UK;

    rnDivision of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research.TheRidgeway, Mill Hill, London NW7 1AA, UK;

    rnDepartment of Genetics and Development, College of Physicians and Surgeonsof Columbia University, 701 West 168th Street, New York, New York 10032.USA;

    rnGraduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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