BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4
BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4
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DOI：
10.1101/gad.1682108
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发表时间：
2008-11-01
影响因子：
10.5
通讯作者：
Harvey, Richard P.
中科院分区：
文献类型：
--
作者：
Furtado, Milena B.;Solloway, Mark J.;Harvey, Richard P.
发育途径中的双稳态是指从分级或噪声输入产生二进制输出。信号阈值对于双稳态是至关重要的。脊椎动物胚胎中左/右（LR）轴的特化涉及由前馈和反馈回路控制的左侧板中胚层（LPM）中转化生长因子β（TGF β）成员NODAL的快速表达。在这里，我们提供的证据表明，骨形态发生蛋白（BMP）/SMAD1信号设置一个抑制阈值的LPM的LR信号的完整性至关重要。LPM中Smad1的条件性缺失导致早熟和双侧通路激活。来自节点的左侧和右侧的NODAL表达有助于双侧激活，表明突变LPM对来自LR系统的噪声输入的敏感性。在体外，BMP信号传导抑制NODAL通路激活及其下游SMAD2/4-FOXH1转录复合物的形成。通过SMAD4的过表达恢复活性，并且在胚胎中，右侧LPM中SMAD4的升高强烈激活LR基因表达，超活化BMP信号传导逆转了这种效应。我们的结论是BMP/SMAD1信号为LPM中的NODAL依赖性Nodal激活设置了一个双侧抑制性阈值，限制了SMAD4的可用性。这个抑制阈值对于LR系统的重复输出是必不可少的。
Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGF beta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system.