The pattern of nodal morphogen signaling is shaped by co-receptor expression.
The pattern of nodal morphogen signaling is shaped by co-receptor expression.
复制标题
结形态因子信号的模式是由共受体的表达形成的。
DOI：
10.7554/elife.54894
复制
发表时间：
2021-05-26
期刊：
影响因子：
7.7
通讯作者：
Schier AF
中科院分区：
文献类型：
--
作者：
Lord ND;Carte AN;Abitua PB;Schier AF
胚胎必须长距离向其组成细胞传达指令。这些指令通常被编码为称为形态发生素的信号浓度。在教科书看来，形态发生素分子从局部来源扩散形成浓度梯度，靶细胞通过测量局部形态发生素浓度来决定命运。然而，自然模式系统通常包含大量辅助因子和广泛的信号反馈，这表明胚胎需要额外的机制来生成信号模式。在这里，我们研究了斑马鱼胚胎发生过程中中内胚层诱导剂 Nodal 信号模式形成的机制。我们发现，在没有信号反馈和中继的情况下，节点信号活动跨越正常范围，这表明扩散足以形成节点梯度。我们进一步表明，内源性 Nodal 配体的范围是由 EGF-CFC 共受体 Oep 设定的：在不存在 Oep 的情况下，Nodal 活性扩散，在整个胚胎中形成几乎均匀的分布。反过来，增加 Oep 水平会使细胞对 Nodal 配体敏感。我们用一个计算模型概括了这些实验结果，其中 Oep 通过设置靶细胞的捕获率来调节 Nodal 配体的扩散。该模型预测并在体内证实了令人惊讶的观察结果，即未能补充 Oep 会将 Nodal 信号梯度转变为行波。这些结果表明，Nodal 形态发生素信号传导的模式是由共受体介导的配体扩散限制和响应细胞的敏化形成的。
Embryos must communicate instructions to their constituent cells over long distances. These instructions are often encoded in the concentration of signals called morphogens. In the textbook view, morphogen molecules diffuse from a localized source to form a concentration gradient, and target cells adopt fates by measuring the local morphogen concentration. However, natural patterning systems often incorporate numerous co-factors and extensive signaling feedback, suggesting that embryos require additional mechanisms to generate signaling patterns. Here, we examine the mechanisms of signaling pattern formation for the mesendoderm inducer Nodal during zebrafish embryogenesis. We find that Nodal signaling activity spans a normal range in the absence of signaling feedback and relay, suggesting that diffusion is sufficient for Nodal gradient formation. We further show that the range of endogenous Nodal ligands is set by the EGF-CFC co-receptor Oep: in the absence of Oep, Nodal activity spreads to form a nearly uniform distribution throughout the embryo. In turn, increasing Oep levels sensitizes cells to Nodal ligands. We recapitulate these experimental results with a computational model in which Oep regulates the diffusive spread of Nodal ligands by setting the rate of capture by target cells. This model predicts, and we confirm in vivo, the surprising observation that a failure to replenish Oep transforms the Nodal signaling gradient into a travelling wave. These results reveal that patterns of Nodal morphogen signaling are shaped by co-receptor-mediated restriction of ligand spread and sensitization of responding cells.