Systems Biology Derived Mechanism Of Bmp Gradient Formation

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral (DV) axis of all vertebrates. This gradient is established by the extracellular interaction of the asymmetric expression of the BMP ligand and its extracellular regulators. Though the basic agonism and antagonism of BMP by these regulators has been established over the last two decades, the mechanism by which they come together to form a robust BMP signaling gradient remains poorly understood. 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, I created a quantitative method of measuring BMP signaling, and used it to precisely quantify the BMP activity gradient in wild-type and mutant embryos. We combined these data with a computational model-based screen to test hypotheses for gradient formation. Surprisingly, the analysis did not support a counter-gradient mechanism and rules out both a BMP shuttling mechanism, and a bmp transcriptionally-informed gradient mechanism. Instead a fourth model emerged, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a BMP sink that drives BMP diffusion 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. We have developing a way to quantify the BMP signaling gradient, a mathematical model incorporating the core extracellular BMP regulators, and mathematical definitions for the different gradient mechanisms. In doing so, we have opened the door for future studies to add in additional BMP regulators to the model such as Bmper, Twisted Gastrulation and Sizzled, to identify and measure key biophysical parameters, and to address questions about how cells sense a BMP morphogen gradient and translate that signal into target gene expression.