Multi-modal effects of BMP signaling on Nodal expression in the lateral plate mesoderm during left-right axis formation in the chick embryo.
Multi-modal effects of BMP signaling on Nodal expression in the lateral plate mesoderm during left-right axis formation in the chick embryo.
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DOI：
10.1016/j.ydbio.2012.11.027
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发表时间：
2013-02
影响因子：
2.7
通讯作者：
K. Katsu;Norifumi Tatsumi;Daisuke Niki;K. Yamamura;Y. Yokouchi
中科院分区：
文献类型：
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作者：
K. Katsu;Norifumi Tatsumi;Daisuke Niki;K. Yamamura;Y. Yokouchi
在脊椎动物胚胎左右不对称的发育过程中，Nodal在决定左撇子的过程中起着核心作用。骨形态发生蛋白（Bone morphogenetic protein， BMP）信号在调节鸡胚Nodal表达中起着重要作用，但目前关于BMP信号对鸡胚Nodal表达的影响是积极的还是消极的还存在争议。由于BMP是一种形态形成因子，我们推测不同浓度的BMP可能在侧板中胚层（LPM）细胞中引起不同的反应。为了验证这一假设，我们分析了不同浓度的BMP4和NOGGIN对LPM中Nodal表达的影响。我们发现对淋巴结表达的影响随着BMP浓度的变化而发生复杂的变化。与之前的报道一致，我们发现高水平的BMP信号诱导LPM中的Nodal表达，而低水平的BMP信号抑制表达。然而，高水平的中间水平BMP信号抑制左侧LPM的node表达，而低水平的中间水平诱导右侧LPM的node表达。由此可见，高、中、低水平BMP信号上调了Nodal的表达，而高、中、低水平BMP信号下调了Nodal的表达。接下来，我们试图通过BMP信号确定这种复杂的调节节点表达的机制。在BMP信号的中低水平，调节依赖于一个NODAL正反馈回路，这表明BMP和NODAL信号之间可能存在串扰。组成活性BMP受体、组成活性ACTIVIN/NODAL受体和SMAD4的过表达表明，在LPM细胞中，SMAD1和SMAD2竞争与SMAD4结合。高水平和低水平BMP信号的节点调节分别依赖于Cfc的上调或下调。我们提出了一个BMP信号对节点表达的可变影响模型，其中不同水平的BMP信号通过BMP- psmad1 /4信号和node - psmad2 /4信号之间的平衡来调节节点表达。
During development of left–right asymmetry in the vertebrate embryo, Nodal plays a central role for determination of left-handedness. Bone morphogenetic protein (BMP) signaling has an important role for regulation of Nodal expression, although there is controversy over whether BMP signaling has a positive or negative effect on Nodal expression in the chick embryo. As BMP is a morphogen, we speculated that different concentrations might induce different responses in the cells of the lateral plate mesoderm (LPM). To test this hypothesis, we analyzed the effects of various concentrations of BMP4 and NOGGIN on Nodal expression in the LPM. We found that the effect on Nodal expression varied in a complex fashion with the concentration of BMP. In agreement with previous reports, we found that a high level of BMP signaling induced Nodal expression in the LPM, whereas a low level inhibited expression. However, a high intermediate level of BMP signaling was found to suppress Nodal expression in the left LPM, whereas a low intermediate level induced Nodal expression in the right LPM. Thus, the high and the low intermediate levels of BMP signaling up-regulated Nodal expression, but the high intermediate and low levels of BMP signaling down-regulated Nodal expression. Next, we sought to identify the mechanisms of this complex regulation of Nodal expression by BMP signaling. At the low intermediate level of BMP signaling, regulation depended on a NODAL positive-feedback loop suggesting the possibility of crosstalk between BMP and NODAL signaling. Overexpression of a constitutively active BMP receptor, a constitutively active ACTIVIN/NODAL receptor and SMAD4 indicated that SMAD1 and SMAD2 competed for binding to SMAD4 in the cells of the LPM. Nodal regulation by the high and low levels of BMP signaling was dependent on Cfc up-regulation or down-regulation, respectively. We propose a model for the variable effects of BMP signaling on Nodal expression in which different levels of BMP signaling regulate Nodal expression by a balance between BMP-pSMAD1/4 signaling and NODAL-pSMAD2/4 signaling.