Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm
Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm
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DOI：
10.1242/dev.124024
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发表时间：
2015-07-15
期刊：
影响因子：
4.6
通讯作者：
Kimelman, David
中科院分区：
文献类型：
--
作者：
Bouldin, Cortney M.;Manning, Alyssa J.;Kimelman, David
脊椎动物体的前向后生长是由位于后部的双能神经中胚层祖细胞群体推动的。这些祖细胞具有有限的增殖速率，并且它们的维持对于完成前后轴至关重要。它们如何离开祖细胞状态并致力于分化在很大程度上尚不清楚，部分原因是对这一过程至关重要的因素的广泛调节会导致整个生物体的影响。使用一种新的检测方法，我们表明，斑马鱼Tbx16（Spadetail）是能够推进中胚层分化细胞自主。Tbx16不仅通过激活下游中胚层基因，而且通过抑制双能祖基因，部分通过直接抑制sox 2，将细胞锁定在中胚层状态。我们证明，TBX16被激活的细胞从一个中间的Wnt环境移动到一个高Wnt环境，并显示Wnt信号激活TBX16启动子。重要的是，高水平的Wnt信号能够自主地加速中胚层分化细胞，就像我们用Tbx16观察到的那样。最后，因为我们的中胚层定型试验是定量的，我们能够表明中胚层分化的加速是令人惊讶的不完全的，暗示在此过程中细胞运动和分化的潜在分离。总之，我们的数据表明了一个模型，其中高水平的Wnt信号传导通过直接激活tbx16诱导向中胚层的过渡，这反过来又起到不可逆地翻转转录因子开关的作用，导致中胚层命运的维持和双能祖细胞状态的抑制，即使细胞离开初始的高Wnt环境。
Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment.