Department of Cell and DevelopmentalBiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States.
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, United States.
Elife. 2017 Aug 9;6:e22199. doi: 10.7554/eLife.22199.
A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates. The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels. To delineate the mechanism in zebrafish, we precisely quantified the BMP activity gradient in wild-type and mutant embryos and combined these data with a mathematical model-based computational screen to test hypotheses for gradient formation. Our analysis ruled out a BMP shuttling mechanism and a transcriptionally-informed gradient mechanism. Surprisingly, rather than supporting a counter-gradient mechanism, our analyses support a fourth model, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a sink that drives BMP flux dorsally and gradient formation. We measured Bmp2 diffusion and found that it supports the source-sink model, suggesting a new mechanism to shape BMP gradients during development.
骨形态发生蛋白 (BMP) 的形态发生梯度模式化了脊椎动物和无脊椎动物的背腹胚胎轴。在脊椎动物中，BMP 梯度形成的主要观点是通过 BMP 拮抗剂的逆梯度，通常伴随着配体穿梭以产生峰值信号水平。为了阐明斑马鱼中的机制，我们精确地量化了野生型和突变型胚胎中的 BMP 活性梯度，并将这些数据与基于数学模型的计算筛选相结合，以测试梯度形成的假设。我们的分析排除了 BMP 穿梭机制和转录信息梯度机制。令人惊讶的是，我们的分析并没有支持逆梯度机制，而是支持第四个模型，即源-汇机制，该机制依赖于作为汇的受限 BMP 拮抗剂分布，该分布充当将 BMP 通量向背部驱动并形成梯度的汇。我们测量了 Bmp2 的扩散，发现它支持源-汇模型，这表明在发育过程中形成 BMP 梯度的一种新机制。
