Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo
Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo
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DOI：
10.1242/dev.000901
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发表时间：
2007-06-01
期刊：
影响因子：
4.6
通讯作者：
Belo, Jose Antonio
中科院分区：
文献类型：
--
作者：
Tavares, Ana Teresa;Andrade, Sofia;Belo, Jose Antonio
转化生长因子-β相关分子Nodal在脊椎动物胚胎左右排列中起着重要而保守的作用。以往的报道表明，斑马鱼和小鼠Cerberus相关蛋白Charon和Cerberus-like-2(Cerl-2)分别作用于结节区域，阻止节点信号交叉到右侧，而鸡Cerberus(CCER)在左侧中胚层中的功能尚不清楚。在本研究中，我们研究了CCER在左右发育过程中的转录调控和功能。通过分析CCER 5‘端基因组序列在鸡胚胎电穿孔中的增强子活性，我们鉴定了一个含有两个FoxH1和一个SMAD结合位点的CCER左侧增强子。我们证明这些结节反应元件是激活左侧中胚层转录的必要条件和充分条件。在转基因小鼠胚胎中，CCER调控序列的行为与鸡胚胎中的一样，这表明Cerberus相关基因的顺式调控序列在脊椎动物进化过程中发生了分歧。此外，我们从CCER过表达和敲除实验中的发现表明，CCER是节点不对称信号的负反馈调节因子。我们认为CCER和小鼠Cerl-2进化了不同的调控机制，但在左右发育过程中保留了一个保守的功能，即将Nodal的活动限制在胚胎的左侧。
The TGF-beta-related molecule Nodal plays an essential and conserved role in left-right patterning of the vertebrate embryo. Previous reports have shown that the zebrafish and mouse Cerberus-related proteins Charon and Cerberus-like-2 (Cerl-2), respectively, act in the node region to prevent the Nodal signal from crossing to the right side, whereas chick Cerberus (cCer) has an unclear function in the left-side mesoderm. In this study, we investigate the transcriptional regulation and function of cCer in left-right development. By analyzing the enhancer activity of cCer 5' genomic sequences in electroporated chick embryos, we identified a cCer left-side enhancer that contains two FoxH1 and one SMAD binding site. We show that these Nodal-responsive elements are necessary and sufficient for the activation of transcription in the left-side mesoderm. In transgenic mouse embryos, cCer regulatory sequences behave as in chick embryos, suggesting that the cis-regulatory sequences of Cerberus-related genes have diverged during vertebrate evolution. Moreover, our findings from cCer overexpression and knockdown experiments indicate that cCer is a negative-feedback regulator of Nodal asymmetric signaling. We propose that cCer and mouse Cerl-2 have evolved distinct regulatory mechanisms but retained a conserved function in left-right development, which is to restrict Nodal activity to the left side of the embryo.