Integration of nodal and BMP signals in the heart requires FoxH1 to create left-right differences in cell migration rates that direct cardiac asymmetry.
Integration of nodal and BMP signals in the heart requires FoxH1 to create left-right differences in cell migration rates that direct cardiac asymmetry.
复制标题
DOI：
10.1371/journal.pgen.1003109
复制
发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Burdine RD
中科院分区：
文献类型：
--
作者：
Lenhart KF;Holtzman NG;Williams JR;Burdine RD
未能正确建立左右（L/R）轴是人类先天性心脏缺陷的主要原因，但胚胎的L/R模式如何导致不对称的心脏形态发生仍不清楚。我们发现，不对称的Nodal信号的左侧和BMP信号的行为平行建立斑马鱼心脏偏侧化通过调节细胞迁移速度跨越L/R轴。此外，我们证明了Nodal在心脏中产生不对称性中起着至关重要的作用，并且在不对称Nodal信号传导的存在下，通过Bmp 4的Bmp信号传导被抑制。此外，我们确定了一个以前不受重视的作用，为Nodal转录因子FoxH 1在介导细胞对Bmp的反应，进一步连接控制这两个途径在心脏。这些TGFβ途径之间的相互作用是复杂的，Nodal信号传导可能起到限制对Bmp途径活化的反应的作用，并且Bmp信号的剂量对于限制迁移速率至关重要。这些发现对于理解导致人类先天性心脏病的复杂遗传相互作用具有重要意义。左-右（L/R）模式的缺陷可能导致心脏形成的严重缺陷。事实上，三种最常见的先天性心脏病，即大动脉转位、腔室间隔缺损和腔室异构，都可能是由L/R不对称的早期缺陷引起的。Nodal和Bmp信号通路影响心脏不对称的发展，但这些信号在此过程中的作用尚不清楚。在这份报告中，我们已经阐明了心脏中Nodal与Bmp通路的具体作用。我们发现，Nodal信号增加心肌细胞迁移的速率，而Bmp信号降低心肌细胞的速度。我们证明，不对称的Nodal信号在指导心脏的不对称性中起着关键作用，与此相反，报告表明通过Bmp 4的信号是更关键的途径。事实上，我们发现Bmp 4信号传导在存在不对称Nodal信号的情况下被用于心脏中的正确不对称性。此外，我们已经确定了一种新的整合这两个途径之间的转录因子FoxH 1的水平，这是需要心脏细胞的反应，Nodal和Bmp信号。总之，这项工作大大增加了我们对调节心脏不对称性的信号如何发挥作用的理解，并整合以一致地建立心脏偏侧性。这些结果还表明，尚未发现由单个基因内的单个突变引起的人类先天性心脏缺陷可能是由于这两个单独途径的组分内的突变组合而发展的。
Failure to properly establish the left–right (L/R) axis is a major cause of congenital heart defects in humans, but how L/R patterning of the embryo leads to asymmetric cardiac morphogenesis is still unclear. We find that asymmetric Nodal signaling on the left and Bmp signaling act in parallel to establish zebrafish cardiac laterality by modulating cell migration velocities across the L/R axis. Moreover, we demonstrate that Nodal plays the crucial role in generating asymmetry in the heart and that Bmp signaling via Bmp4 is dispensable in the presence of asymmetric Nodal signaling. In addition, we identify a previously unappreciated role for the Nodal-transcription factor FoxH1 in mediating cell responsiveness to Bmp, further linking the control of these two pathways in the heart. The interplay between these TGFβ pathways is complex, with Nodal signaling potentially acting to limit the response to Bmp pathway activation and the dosage of Bmp signals being critical to limit migration rates. These findings have implications for understanding the complex genetic interactions that lead to congenital heart disease in humans. Defects in left–right (L/R) patterning can lead to severe defects in the formation of the heart. In fact, three of the most common forms of congenital heart disease, transposition of the great arteries, chamber septation defects, and chamber isomerisms, can be caused by earlier defects in L/R asymmetry. The Nodal and Bmp signaling pathways influence the development of cardiac asymmetry, but how these signals function in this process is not well understood. In this report, we have clarified the specific roles for the Nodal versus Bmp pathways in the heart. We find that Nodal signals increase the rate of cardiac cell migration, while Bmp signals decrease cardiac cell velocities. We demonstrate that asymmetric Nodal signaling plays a critical role in directing asymmetry in the heart in contrast to reports suggesting that signaling via Bmp4 is the more critical pathway. In fact, we find that Bmp4 signaling is dispensable for correct asymmetry in the heart in the presence of asymmetric Nodal signals. In addition, we have identified a novel integration between these two pathways at the level of the transcription factor FoxH1, which is required for cardiac cell responsiveness to both Nodal and Bmp signals. Taken together, this work significantly increases our understanding of how the signals regulating cardiac asymmetry function and integrate to consistently establish cardiac laterality. These results also suggest that human congenital heart defects that have not been found to result from single mutations within individual genes may develop due to combinations of mutations within components of these two separate pathways.
登录
查看更多内容
影响因子：
3.6
作者：
Byfield, SD;Major, C;Roberts, AB
通讯作者：
Roberts, AB
影响因子：
9.2
作者：
Amack, JD;Yost, HJ
通讯作者：
Yost, HJ
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：
10.5
作者：
Furtado, Milena B.;Solloway, Mark J.;Harvey, Richard P.
通讯作者：
Harvey, Richard P.
影响因子：
2.7
作者：
Hagos, Engda G.;Fan, Xiang;Dougan, Scott T.
通讯作者：
Dougan, Scott T.