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首页> 外文期刊>The Journal of biological chemistry >Antagonism between the transcription factors NANOG and OTX2 specifies rostral or caudal cell fate during neural patterning transition
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Antagonism between the transcription factors NANOG and OTX2 specifies rostral or caudal cell fate during neural patterning transition

机译：转录因子NANOG和OTX2之间的拮抗作用指定了神经模式转换过程中的鼻侧或尾侧细胞命运

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During neurogenesis, neural patterning is a critical step during which neural progenitor cells differentiate into neurons with distinct functions. However, the molecular determinants that regulate neural patterning remain poorly understood. Here we optimized the “dual SMAD inhibition” method to specifically promote differentiation of human pluripotent stem cells (hPSCs) into forebrain and hindbrain neural progenitor cells along the rostral–caudal axis. We report that neural patterning determination occurs at the very early stage in this differentiation. Undifferentiated hPSCs expressed basal levels of the transcription factor orthodenticle homeobox 2 (OTX2) that dominantly drove hPSCs into the “default” rostral fate at the beginning of differentiation. Inhibition of glycogen synthase kinase 3β (GSK3β) through CHIR99021 application sustained transient expression of the transcription factor NANOG at early differentiation stages through Wnt signaling. Wnt signaling and NANOG antagonized OTX2 and, in the later stages of differentiation, switched the default rostral cell fate to the caudal one. Our findings have uncovered a mutual antagonism between NANOG and OTX2 underlying cell fate decisions during neural patterning, critical for the regulation of early neural development in humans.
机译：在神经发生过程中，神经模式是神经祖细胞分化为具有不同功能的神经元的关键步骤。但是，调节神经模式的分子决定因素仍然知之甚少。在这里，我们优化了“双重SMAD抑制”方法，以专门促进人类多能干细胞（hPSC）沿延髓-尾轴分化为前脑和后脑神经祖细胞。我们报道神经模式确定发生在这种分化的非常早期。未分化的hPSCs表达了转录因子直齿同源盒2（OTX2）的基础水平，该水平在分化开始时将hPSC显着地带入了“默认”的尾缘命运。通过CHIR99021施加抑制糖原合酶激酶3β（GSK3β）可在Wnt信号转导的早期分化阶段维持转录因子NANOG的瞬时表达。 Wnt信号传导和NANOG拮抗OTX2，并在分化的后期将默认的延髓细胞命运转移到了尾鳍细胞。我们的发现揭示了在神经形成过程中NANOG和OTX2潜在的细胞命运决定之间的相互对抗，这对人类早期神经发育的调控至关重要。

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