Chang H, Zwijsen A, Vogel H, Huylebroeck D, Matzuk M M
Department of Pathology, Program in Developmental Biology, Houston, Texas, 77030, USA.
Dev Biol. 2000 Mar 1;219(1):71-8. doi: 10.1006/dbio.1999.9594.
Left-right (L-R) asymmetry of the vertebrate body plan is established from an originally morphologically symmetric embryo. Recent studies have implicated several TGF-beta family signaling proteins (i.e., nodal, lefty-1, lefty-2, activin receptor type IIB, and Smad2) in L-R axis determination in the mouse. However, the genetic pathways underlying L-R patterning are still unclear. Smad5 is a downstream component in the TGF-beta family signaling cascade, and lack of Smad5 results in embryonic lethality between E9.5 and E11.5. In this report, we demonstrate that Smad5 mutant embryos have defects in heart looping and embryonic turning which are the first signs of L-R asymmetry in mice. To gain more insights into the molecular basis of the laterality defects in the Smad5-deficient embryos, we examined the expression of lefty-1, lefty-2, nodal, and Pitx2 since the asymmetric expression of these genes always closely correlates with the direction of heart looping and embryonic turning. In the absence of Smad5, lefty-1 was expressed at very low or undetectable levels, while nodal, lefty-2, and Pitx2 were expressed bilaterally. These data suggest that Smad5 is upstream of lefty-1, nodal, and lefty-2, and as a consequence also of Pitx2, and Smad5 is essential for L-R axis determination.
脊椎动物身体结构的左右不对称是从最初形态对称的胚胎开始建立的。最近的研究表明，几种转化生长因子-β（TGF-β）家族信号蛋白（即节点蛋白、左撇子-1、左撇子-2、激活素受体IIB型和Smad2）参与了小鼠左右轴的确定。然而，左右模式形成的遗传途径仍不清楚。Smad5是TGF-β家族信号级联反应的下游成分，缺乏Smad5会导致胚胎在E9.5至E11.5之间死亡。在本报告中，我们证明Smad5突变胚胎在心脏环化和胚胎旋转方面存在缺陷，而这是小鼠左右不对称的最初迹象。为了更深入了解Smad5缺陷胚胎中左右缺陷的分子基础，我们检测了左撇子-1、左撇子-2、节点蛋白和Pitx2的表达，因为这些基因的不对称表达总是与心脏环化和胚胎旋转的方向密切相关。在缺乏Smad5的情况下，左撇子-1以非常低的水平表达或无法检测到，而节点蛋白、左撇子-2和Pitx2则双侧表达。这些数据表明，Smad5在左撇子-1、节点蛋白和左撇子-2的上游，因此也在Pitx2的上游，并且Smad5对于左右轴的确定至关重要。
