Loss of FGF-dependent mesoderm identity and rise of endogenous retinoid signalling determine cessation of body axis elongation.
Loss of FGF-dependent mesoderm identity and rise of endogenous retinoid signalling determine cessation of body axis elongation.
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DOI：
10.1371/journal.pbio.1001415
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Storey KG
中科院分区：
文献类型：
--
作者：
Olivera-Martinez I;Harada H;Halley PA;Storey KG
通过分析胚胎发生过程中尾芽关键细胞群的细胞和分子变化，这项工作揭示了决定脊椎动物体长的关键信号事件。决定脊椎动物体长的内源性机制尚不清楚，但肯定涉及尾芽中脊索神经铰链（CNH）/轴干细胞和中胚层祖细胞的损失。在早期胚胎中，成纤维细胞生长因子 (FGF) 维持着一个逐渐形成身体的细胞池，并且分化的开始是由 FGF 信号传导的类维生素A抑制驱动的。这提出了以下可能性：FGF 维持了关键的尾芽细胞群，并且类视黄醇活性的增加是体轴伸长停止的基础。在这里，我们发现 CNH 和中胚层祖细胞结构域中中胚层基因 (Brachyury) 的突然丢失与后期雏鸡尾芽中 FGF 信号传导的下降相关。这伴随着神经基因表达的扩展，并且细胞命运标记的类似变化在人类尾芽中也很明显。鸡尾芽的命运图谱进一步揭示了神经基因表达的传播是由于 CNH 衍生细胞持续进入中胚层祖细胞结构域的位置所致。利用体外和体内功能获得和丧失的方法，我们发现 FGF/Erk 信号传导的减弱介导了 Wnt 信号传导上游 Brachyury 的丧失，而高水平 FGF 维持 Brachyury 并可诱导异位 CNH 样细胞灶。我们进一步证明了尾芽中内源性类视黄醇信号传导的增加，并表明此处 FGF 不再阻碍类视黄醇的合成和活性。此外，后期阶段类视黄醇信号传导的减少会升高 FGF 活性并异位维持中胚层基因表达，这表明内源性类视黄醇信号传导导致中胚层特性的丧失。最后，轴终止是通过局部细胞死亡来结束的，局部细胞死亡可以通过阻断类维生素A信号传导来减少，但涉及不依赖于FGFR的机制。我们提出，身体伸长的停止涉及后期尾芽中 FGF 依赖性中胚层特性的丧失，并提供证据表明内源性类视黄醇活性的升高介导了这一步骤，并最终促进雏鸡尾芽中的细胞死亡。决定身体长度的机制尚不清楚，但可能在脊椎动物胚胎的伸长尾端起作用。在早期胚胎中，成纤维细胞生长因子（FGF）信号维持尾芽中细胞的增殖池，从而逐渐形成身体。它还保护这些细胞免受视黄酸的分化影响，视黄酸是由延伸体的成熟中胚层组织产生的。我们在这里表明，在鸡胚胎中，当中胚层基因 brachyury 突然从发育后期的尾芽中的轴向干细胞群和推定中胚层细胞中丢失时，“终局”（即体轴伸长的终止）就会到来。使用功能获得和功能丧失方法，我们证明该步骤是由 FGF 信号传导丧失介导的。我们提供的证据表明，这是由于尾芽中的类维生素A信号传导增加所致，并且尾芽中的FGF信号传导不再阻碍类维生素A的合成和活性。最后，我们揭示了这些事件之后是尾芽中的局部细胞死亡，这种死亡可以通过类维生素A信号传导的减弱来减少，但涉及一种独立于通过其常用受体进行的FGF信号传导的机制。我们认为，身体伸长的停止涉及晚期尾芽中 FGF 依赖性中胚层特性的丧失，并且这是由内源性视黄醇活性升高介导的，最终促进雏鸡尾芽中的细胞死亡。
By analyzing cellular and molecular changes in key cell populations in the tailbud during embryogenesis, this work uncovers critical signaling events that determine vertebrate body length. The endogenous mechanism that determines vertebrate body length is unknown but must involve loss of chordo-neural-hinge (CNH)/axial stem cells and mesoderm progenitors in the tailbud. In early embryos, Fibroblast growth factor (FGF) maintains a cell pool that progressively generates the body and differentiation onset is driven by retinoid repression of FGF signalling. This raises the possibility that FGF maintains key tailbud cell populations and that rising retinoid activity underlies cessation of body axis elongation. Here we show that sudden loss of the mesodermal gene (Brachyury) from CNH and the mesoderm progenitor domain correlates with FGF signalling decline in the late chick tailbud. This is accompanied by expansion of neural gene expression and a similar change in cell fate markers is apparent in the human tailbud. Fate mapping of chick tailbud further revealed that spread of neural gene expression results from continued ingression of CNH-derived cells into the position of the mesoderm progenitor domain. Using gain and loss of function approaches in vitro and in vivo, we then show that attenuation of FGF/Erk signalling mediates this loss of Brachyury upstream of Wnt signalling, while high-level FGF maintains Brachyury and can induce ectopic CNH-like cell foci. We further demonstrate a rise in endogenous retinoid signalling in the tailbud and show that here FGF no longer opposes retinoid synthesis and activity. Furthermore, reduction of retinoid signalling at late stages elevated FGF activity and ectopically maintained mesodermal gene expression, implicating endogenous retinoid signalling in loss of mesoderm identity. Finally, axis termination is concluded by local cell death, which is reduced by blocking retinoid signalling, but involves an FGFR-independent mechanism. We propose that cessation of body elongation involves loss of FGF-dependent mesoderm identity in late stage tailbud and provide evidence that rising endogenous retinoid activity mediates this step and ultimately promotes cell death in chick tailbud. The mechanism that determines body length is unknown but likely operates at the elongating tail end of vertebrate embryos. In the early embryo, fibroblast growth factor (FGF) signalling maintains a proliferative pool of cells in the tailbud that progressively generates the body. It also protects these cells from the differentiating influence of retinoic acid, which is produced by the maturing mesoderm tissues of the extending body. We show here, in the chick embryo, that the “endgame”—that is, the termination of body axis elongation—comes when the mesodermal gene brachyury is suddenly lost from axial stem cell population and presumptive mesoderm cells in the tailbud late in development. Using gain- and loss-of-function approaches, we demonstrate that this step is mediated by loss of FGF signalling. We present evidence that this is due to rising retinoid signalling in the tailbud and that FGF signalling in the tailbud no longer opposes retinoid synthesis and activity. Finally, we reveal that these events are followed by local cell death in the tailbud, which can be reduced by the attenuation of retinoid signalling but involves a mechanism that is independent of FGF signalling via its usual receptor. We propose that cessation of body elongation involves loss of FGF-dependent mesoderm identity in the late tailbud and that this is mediated by rising endogenous retinoid activity, which ultimately promotes cell death in the chick tailbud.
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