Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.
Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.
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DOI：
10.1038/nature09729
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发表时间：
2011-02-17
期刊：
影响因子：
64.8
通讯作者：
Kondoh, Hisato
中科院分区：
文献类型：
--
作者：
Takemoto, Tatsuya;Uchikawa, Masanori;Yoshida, Megumi;Bell, Donald M.;Lovell-Badge, Robin;Papaioannou, Virginia E.;Kondoh, Hisato
神经板发育的经典观点认为，它来自外胚层，在其从中胚层和内胚层谱系分离之后。然而，最近的细胞谱系示踪实验表明，尾神经板和近轴中胚层产生的共同的双能轴向干细胞起源于尾侧外胚层（CLE）。Tbx 6无效突变小鼠胚胎产生异位神经管的近轴中胚层的费用必须提供一个线索，这种神经与中胚层的命运选择的监管机制。在这里，我们证明了Tbx 6依赖性调节Sox 2决定了轴向干细胞的命运。在野生型胚胎中，神经原始基因Sox 2的增强子N1在CLE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Sox 2表达。相反，注定成为中胚层的细胞在迁移到近轴中胚层隔室之前激活Tbx 6并关闭增强子N1。然而，在Tbx 6突变体胚胎中，增强子N1活性持续存在于近轴中胚层隔室中，引起异位Sox 2激活并将近轴中胚层转化为神经管。一个增强子N1-特异性缺失突变引入Tbx 6突变胚胎阻止这种Sox 2激活中胚层隔室和随后的发展异位神经管，表明Tbx 6调节Sox 2通过增强子N1。Tbx 6依赖性对近轴中胚层隔室中Wnt 3a的抑制与这一调节过程有关。近轴中胚层特异性Sox 2转基因在野生型胚胎中的错误表达导致异位神经管发育。因此，Tbx 6通过失活增强子N1来抑制Sox 2以抑制神经发育，这是从轴向干细胞向近轴中胚层分化的重要步骤。
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 (CLE). Tbx6 null 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 N1 of the neural primordial gene Sox2 is activated in the CLE, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer N1-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 N1. 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 N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.
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