Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos.
Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos.
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DOI：
10.1016/j.ydbio.2011.03.009
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发表时间：
2011-05-15
影响因子：
2.7
通讯作者：
Hamada H
中科院分区：
文献类型：
--
作者：
Kawasumi A;Nakamura T;Iwai N;Yashiro K;Saijoh Y;Belo JA;Shiratori H;Hamada H
小鼠胚胎的左右（L-R）不对称是在淋巴结产生的，依赖于纤毛驱动的流体流动，但最初的不对称是如何从淋巴结传递到侧板的尚不清楚。我们现在已经在人类LEFTY1基因中发现了一个转录增强子（ANE），该基因在小鼠胚胎的周结细胞中表现出明显的l> R不对称活性。解剖发现左侧结周细胞内的ANE被Nodal信号激活，提示在Nodal表达对称的同时，结内的Nodal活性是不对称的。磷酸化的Smad2/3 （pSmad2）确实在淋巴结处表现为L-R不对称分布，优先在左侧淋巴结周围细胞中检测到。这种pSmad2分布的不对称性不是由Nodal的单向转运产生的，而是Nodal拮抗剂Cerl2的L<R不对称表达的结果。在不同的突变胚胎中，pSmad2在卵周细胞中的不对称性与在侧板中胚层（LPM）中的不对称性非常相似。然而，淋巴结周围细胞中的自分泌-旁分泌淋巴结信号对于LPM的L-R模式是必不可少的，因为其通过显性阴性形式Smad3或ALK4的表达抑制仍然与LPM中正常（左侧）淋巴结表达相关。我们的研究结果表明，LPM是结周细胞分泌的Nodal的直接靶点，活跃的Nodal在结内的L>R分布转化为LPM的不对称性。
Left-right (L-R) asymmetry in the mouse embryo is generated in the node and is dependent on cilia-driven fluid flow, but how the initial asymmetry is transmitted from the node to the lateral plate has remained unknown. We have now identified a transcriptional enhancer (ANE) in the human LEFTY1 gene that exhibits marked L>R asymmetric activity in perinodal cells of the mouse embryo. Dissection of ANE revealed that it is activated in the perinodal cells on the left side by Nodal signaling, suggesting that Nodal activity in the node is asymmetric at a time when Nodal expression is symmetric. Phosphorylated Smad2/3 (pSmad2) indeed manifested an L-R asymmetric distribution at the node, being detected in perinodal cells preferentially on the left side. This asymmetry in pSmad2 distribution was found to be generated not by unidirectional transport of Nodal but rather as a result of L<R asymmetric expression of the Nodal antagonist Cerl2. For various mutant embryos examined, the asymmetry in pSmad2 distribution among the perinodal cells closely matched that in lateral plate mesoderm (LPM). However, autocrine-paracrine Nodal signaling in perinodal cells is dispensable for L-R patterning of LPM, given that its inhibition by expression of dominant negative forms of Smad3 or ALK4 was still associated with normal (left-sided) Nodal expression in LPM. Our results suggest that LPM is the direct target of Nodal secreted by the perinodal cells, and that an L>R distribution of active Nodal in the node is translated into the asymmetry in LPM.
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