Systems biology derived source-sink mechanism of BMP gradient formation
- Perelman School of Medicine, University of Pennsylvania, United States
- Purdue University, United States
Abstract
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 bmp 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.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM056326)
- Joseph Zinski
- Mary Mullins
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD073156,T32 HD08318)
- Joseph Zinski
- Ye Bu
- Xu Wang
- Wei Dou
- David Umulis
- Mary Mullins
National Science Foundation
- Joseph Zinski
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#803105, #804931) of the University of Pennsylvania Perelman School of Medicine.
Copyright
© 2017, Zinski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Systems biology derived source-sink mechanism of BMP gradient formation
eLife 6:e22199.
https://doi.org/10.7554/eLife.22199
