Cardiac outflow tract development relies on the complex function of Sox4 and Sox11 in multiple cell types
Cardiac outflow tract development relies on the complex function of Sox4 and Sox11 in multiple cell types
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DOI：
10.1007/s00018-013-1523-x
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发表时间：
2014-08-01
影响因子：
8
通讯作者：
Sock, Elisabeth
中科院分区：
文献类型：
--
作者：
Paul, Mandy H.;Harvey, Richard P.;Sock, Elisabeth
先天性心脏缺陷是人类最常见的出生缺陷，通常会危及生命。通常，它们是由流出道的异常引起的，流出道的形成是中胚层和神经嵴起源的细胞协调发育的结果，并取决于许多不同转录因子的活性。然而，地点，时间和行动方式只分析了其中几个。在这里，我们评估的贡献密切相关的高迁移率族转录因子Sox4和Sox11流出道的发展，并确定其功能。在小鼠中使用细胞类型特异性缺失，我们发现Sox11是中胚层细胞和神经嵴细胞正常发育所必需的。中胚层或神经嵴缺失，或两者同时缺失，导致流出道缺损，范围从右心室双出口到共同动脉干。Sox 4支持Sox 11的功能，但在其他细胞类型中具有与流出道形成相关的额外作用。这两种Sox蛋白在心脏神经嵴发育的早期阶段，包括神经管迁移，增殖和迁移通过咽弓。在神经嵴细胞到达流出道后，它们通过调节细胞骨架、细胞粘附和细胞外基质分子而变得至关重要，以进行适当的分化和相互作用以及与环境的相互作用。我们的研究结果表明，Sox 4和Sox 11在流出道形成过程中在几种细胞类型中具有多种功能，因此可能有助于了解人类先天性心脏病的基础。
Congenital heart defects represent the most common human birth defects and are often life-threatening. Frequently, they are caused by abnormalities of the outflow tract whose formation results from coordinated development of cells from mesodermal and neural crest origin and depends on the activity of many different transcription factors. However, place, time, and mode of action have only been analyzed for a few of them. Here we assess the contribution of the closely related high-mobility-group transcription factors Sox4 and Sox11 to outflow tract development and determine their function. Using cell-type-specific deletion in the mouse, we show that Sox11 is required for proper development in both mesodermal cells and neural crest cells. Deletion in either mesoderm or neural crest, or both, leads to outflow tract defects ranging from double outlet right ventricle to common arterial trunk. Sox4 supports Sox11 in its function, but has additional roles with relevance for outflow tract formation in other cell types. The two Sox proteins are dispensable during early phases of cardiac neural crest development including neural tube emigration, proliferation, and migration through the pharyngeal arches. They become essential after arrival of the neural crest cells in the outflow tract for their proper differentiation and interaction with each other as well as with the environment through regulation of cytoskeletal, cell adhesion, and extracellular matrix molecules. Our results demonstrate that Sox4 and Sox11 have multiple functions in several cell types during outflow tract formation and may thus help to understand the basis of congenital heart defects in humans.