Reversal of left-right asymmetry induced by aberrant Nodal signaling in the node of mouse embryos
Reversal of left-right asymmetry induced by aberrant Nodal signaling in the node of mouse embryos
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DOI：
10.1242/dev.039305
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发表时间：
2009-12-01
期刊：
影响因子：
4.6
通讯作者：
Meno, Chikara
中科院分区：
文献类型：
--
作者：
Oki, Shinya;Kitajima, Keiko;Meno, Chikara
在哺乳动物胚胎中，原条前端的节点是左右（L-R）轴的初始发生器。我们现在表明，在节点上的分子信号的小干扰是负责在inv突变小鼠内脏器官的L-R逆转。在野生型胚胎的节点中，Nodal和编码Nodal抑制剂的Cerl 2（Dand 5）的表达是不对称的，Nodal表达水平在左侧较高，Cerl 2表达水平在右侧较高。然而，在inv/inv胚胎中，Cerl 2表达水平的局部降低导致Nodal信号的上调和随后在节点中Lefty表达的诱导。Lefty 1的异位表达延迟了侧板中胚层中Nodal表达的开始。淋巴结中Cerl 2表达的L-R不对称性也以依赖于Nodal信号的方式逆转。侧板中胚层中的Nodal表达则出现在右侧，可能反映了节点中Nodal和Cerl 2之间的平衡。通过Nodal信号对Cerl 2表达的抑制表明了一种机制，该机制用于放大由结流提供的L-R不对称性的线索以及用于稳定结周围的不对称基因表达。在inv/inv胚胎中，由于Lefty的异位产生，该系统可能反向发挥作用，Lefty以依赖于淋巴结流动的方式抑制左侧的Nodal信号。
The node at the anterior tip of the primitive streak serves as an initial generator of the left-right (L-R) axis in mammalian embryos. We now show that a small disturbance in molecular signaling at the node is responsible for the L-R reversal of visceral organs in the inv mutant mouse. In the node of wild-type embryos, the expression of Nodal and Cerl2 (Dand5), which encodes an inhibitor of Nodal, is asymmetric, with the level of Nodal expression being higher on the left side and that of Cerl2 expression higher on the right. In inv/inv embryos, however, a localized reduction in the level of Cerl2 expression results in upregulation of the Nodal signal and a consequent induction of Lefty expression in the node. The ectopic expression of Lefty1 delays the onset of Nodal expression in the lateral plate mesoderm. L-R asymmetry of Cerl2 expression in the node also becomes reversed in a manner dependent on the Nodal signal. Nodal expression in the lateral plate mesoderm then appears on the right side, probably reflecting the balance between Nodal and Cerl2 in the node. The inhibition of Cerl2 expression by the Nodal signal suggests a mechanism for amplification of the cue for L-R asymmetry provided by nodal flow and for stabilization of asymmetric gene expression around the node. In inv/inv embryos, this system may function in reverse as a result of ectopic production of Lefty, which inhibits the Nodal signal on the left side in a manner dependent on leftward nodal flow.