Oki Shinya, Kitajima Keiko, Marques Sara, Belo José António, Yokoyama Takahiko, Hamada Hiroshi, Meno Chikara
Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Development. 2009 Dec;136(23):3917-25. doi: 10.1242/dev.039305.
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.
原条前端的节点是哺乳动物胚胎左右（L-R）轴的初始发生器。我们现在表明，节点处分子信号的微小扰动是inv突变小鼠内脏器官左右反转的原因。在野生型胚胎的节点中，Nodal和Cerl2（Dand5，编码Nodal的一种抑制剂）的表达是不对称的，Nodal的表达水平在左侧较高，而Cerl2的表达水平在右侧较高。然而，在inv/inv胚胎中，Cerl2表达水平的局部降低导致Nodal信号上调，并进而诱导节点中Lefty的表达。Lefty1的异位表达延迟了侧板中胚层中Nodal表达的起始。节点中Cerl2表达的左右不对称性也以依赖于Nodal信号的方式发生反转。然后侧板中胚层中的Nodal表达出现在右侧，这可能反映了节点中Nodal和Cerl2之间的平衡。Nodal信号对Cerl2表达的抑制表明了一种机制，可放大节点流提供的左右不对称线索，并稳定节点周围的不对称基因表达。在inv/inv胚胎中，由于Lefty的异位产生，该系统可能会反向运作，Lefty以依赖于向左节点流的方式抑制左侧的Nodal信号。
