Bmp and nodal independently regulate lefty1 expression to maintain unilateral nodal activity during left-right axis specification in zebrafish.
Bmp and nodal independently regulate lefty1 expression to maintain unilateral nodal activity during left-right axis specification in zebrafish.
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DOI：
10.1371/journal.pgen.1002289
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Bakkers J
中科院分区：
文献类型：
--
作者：
Smith KA;Noël E;Thurlings I;Rehmann H;Chocron S;Bakkers J
在脊椎动物中，左右（LR）轴的规格是由胚胎后部区域的纤毛结构决定的。在这个纤毛结构中的流体流动负责在侧板中胚层中诱导单侧左侧的Nodal活动，这反过来又调节器官的偏侧性。BMP信号传导活性已被暗示在抑制右侧的Nodal表达中，然而其作用机制一直存在争议。在影响LR模式的突变的正向遗传筛选中，我们确定了斑马鱼linkspoot（lin）突变体，其特征在于心脏偏侧和轻度背腹图案缺陷。定位lin突变揭示了BMP受体1aa（bmpr1aa）基因的失活错义突变。胚胎与突变lin/bmpr1aa和一个新的突变在其paradigm，bmpr1ab，显示了各种背腹和LR图案的缺陷，随着bmpr1a剂量的减少相应的严重程度增加。在Bmpr1a缺陷胚胎中，我们观察到Nodal相关基因spaw的双侧表达，以及中线Nodal拮抗剂lefty1的表达减少。使用遗传模型诱导或抑制Bmp活性结合Nodal抑制或激活，我们发现Bmp和Nodal调节lefty1在中线的表达相互独立。此外，我们还观察到，在LPM中观察到的Nodal活性下调需要通过Bmp信号调节lefty1，这为这种现象提供了一种新的解释。从这些结果中，我们提出了一个两步模型，其中BMP调节LR图案。在淋巴结血流和淋巴结激活开始之前，需要Bmp诱导中线中的lefty1表达。当淋巴结血流已经建立，并且Nodal活性明显时，Nodal和Bmp都是lefty1表达所需的，以确保单侧Nodal激活和正确的LR模式。虽然脊椎动物从外部观察时是两侧对称的，但在体腔内，器官相对于左侧和右侧不对称地定位。所有器官都是镜像的情况下，被称为内脏逆位，与任何医疗缺陷无关。然而，严重的医疗问题发生在婴儿与部分器官逆转（位置矛盾或异位），这是在胚胎发育过程中出现的。胚胎中的左右不对称是通过Nodal的单侧表达建立的，Nodal是分泌生长因子的TGF-β超家族的成员，其作用从人类到蜗牛都是保守的。通过在斑马鱼中进行偏侧性突变体的遗传筛选，我们已经确定了linkspoot突变体，其在内部器官的不对称左右定位中显示出部分缺陷。在linkspoot突变体中被破坏的基因编码骨形态发生蛋白（Bmp）的受体，Bmp是分泌生长因子的TGF-β超家族的另一个成员。Bmp过度表达或敲低模型的进一步分析表明，Bmp信号传导是通过启动和维持胚胎中线屏障来实现单侧Nodal表达所必需的。我们的研究结果证明了一种新的和重要的机制，左右不对称的脊椎动物胚胎的建立和调节。
In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning. Although vertebrates are bilaterally symmetric when observed from the outside, inside the body cavity the organs are positioned asymmetrically with respect to the left and right sides. Cases where all the organs are mirror imaged, known as situs inversus, are not associated with any medical defects. Severe medical problems occur however in infants with a partial organ reversal (situs ambigious or heterotaxia), which arises during embryonic development. Left-right asymmetry in the embryo is established by unilateral expression of Nodal, a member of the Tgf-ß superfamily of secreted growth factors, a role that has been conserved from human to snails. By performing a genetic screen in zebrafish for laterality mutants, we have identified the linkspoot mutant, which displayed partial defects in asymmetric left-right positioning of the internal organs. The gene disrupted in the linkspoot mutant encodes a receptor for bone morphogenetic proteins (Bmp), another member of the Tgf-ß superfamily of secreted growth factors. Further analysis of Bmp over-expression or knock-down models demonstrate that Bmp signalling is required for unilateral Nodal expression, through the initiation and maintenance of an embryonic midline barrier. Our results demonstrate a novel and important mechanism by which left-right asymmetry in the vertebrate embryo is established and regulated.
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影响因子：
--
作者：
Chen, J N;van Bebber, F;Goldstein, A M;Serluca, F C;Jackson, D;Childs, S;Serbedzija, G;Warren, K S;Mably, J D;Lindahl, P;Mayer, A;Haffter, P;Fishman, M C
通讯作者：
Fishman, M C
影响因子：
2.7
作者：
Chocron, Sonja;Verhoeven, Manon C.;Bakkers, Jeroen
通讯作者：
Bakkers, Jeroen
影响因子：
2.1
作者：
Meno, C;Ito, Y;Hamada, H
通讯作者：
Hamada, H
影响因子：
4.6
作者：
Mine, Naoki;Anderson, Ryan M.;Klingensmith, John
通讯作者：
Klingensmith, John
影响因子：
16
作者：
Monsoro-Burq, AH;Le Douarin, NM
通讯作者：
Le Douarin, NM