Optimality of Morphogen Signal Transduction Across the Animal Kingdom

Texas A&M Engineering Experiment Station, College Station TX

Investigators

Abstract

Biological signaling pathways, required for proper cellular decisions, paradoxically are both common to all animals, but also diverse in their action, depending on the needs of each animal and/or tissue. For example, the Bone Morphogenetic Protein (BMP) signaling pathway can be found in flies, worms, fish, and humans, and is used in processes ranging from stem cells to inflammation. Given the extensive reuse of this pathway, it is unclear how can it meet the needs, or “performance objectives” (POs), of such a wide range of tissues. For example, in some tissues, BMP signaling must have a fast (and thus, noisy) response, while in others, a noise-free response. To address this question, researchers from Texas A&M, Notre Dame, and Purdue will probe the relationship between the concentration of signaling proteins and which POs are emphasized. The goal is to determine how signaling pathways common to all animals can be both widely used and flexible to the needs of every tissue, which may point to novel engineering principles that can be leveraged for human systems. Each year, undergraduates from each university will take part in an exchange program that will include research and course modules on engineering principles in signaling dynamics. The overall hypothesis of the project is that, while the BMP pathway is highly conserved in topology and protein sequence, differing concentrations of proteins in the BMP pathway (Smad1, Smad4, and phosphatase) allow the pathway to achieve differing emphases among three competing POs: response speed, noise filtering, and linear sensitivity. As such, the four research groups will study the BMP pathway in three organisms and four tissues: the Drosophila embryo, Drosophila wing disc, zebrafish embryo, and human induced pluripotent stem cells (hIPSCs). Advanced confocal microscopy techniques – such as optogenetic control of the pathway, raster image correlation spectroscopy (RICS), and fluorescence recovery after photobleaching (FRAP) – will be used to obtain time courses of concentrations of fluorescently-tagged BMP pathway components, which in turn will be used to quantify the three POs. Precise perturbations to the pathway will be achieved through optogenetics. The outcome of the project is expected to be a cross-species mathematical model of the BMP pathway predictive of each of the four biological systems, as well as the relationship between Smad protein concentration and POs. Predictions will be tested by altering protein concentrations to change which POs are met by the pathway. This project is supported by the Systems and Synthetic Biology Cluster of the Division of Molecular and Cellular Biosciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.