Signaling Logic Underlying Mammalian Germ Layer Differentiation

William Marsh Rice University, Houston TX

Investigators

Abstract

All organisms begin life as a single cell which then grows, divides, and specializes into all of the diverse cell types which form the organs of the body. How this occurs is one of the most fundamental questions in biology and is key to understanding our own origins as well as the diverse forms of life on earth. It is now known that cells can coordinate their differentiation to specialized cell fates by communicating using extracellular proteins which are secreted by a cell and then received by its neighbors, influencing the outcome of their differentiation. Cells experience signaling through multiple pathways simultaneously, and the outcome depends on the dynamics of how these multiple signals are received and interpreted. Understanding how a cell processes the dynamic information received in making a cell fate decision is a central question in developmental biology. A key challenge in solving this question is the complexity of these signals and the regulatory networks which cells use to interpret them. In this project, we will use experiments with stem cells together with a novel mathematical framework to investigate the first decisions that embryonic cells make as they begin to specialize into the cell types that will ultimately form the brain, heart, lungs and other organs. The investigators expect the results to reveal fundamental mechanisms by which these decisions are made, as well as to yield a model which can be used to predict the outcome of different signaling dynamics on cell fate, which will ultimately improve our ability to direct stem cells to any given fate. As part of the performance of this project, the investigators will train a diverse group of scientists from the undergraduate to the postdoctoral level, and will engage in public outreach and education on the topic of stem cells. They will undertake a project to improve a key public resource for science education by editing the articles dealing with stem cell research on Wikipedia. The investigators will also generate resources for both mathematical modeling and experimental studies of stem cell dynamics which will be widely shared with the scientific community. In mammalian embryos, the initial cell fate decisions within the embryo proper occur at gastrulation stage. A cascade of three signaling pathways, BMP, Wnt, and Nodal is essential for gastrulation. Each one initiates the next pathway by transcriptionally activating its ligand, and loss of any of these pathways leads to a failure in gastrulation. It is known that cell fate decisions are made combinatorially as a function of the dynamic activity of these three pathways, however, the relationship between each pathway and the next and how they combine to generate cell fates remains unknown, because of the difficulty of manipulating and measuring signaling and cell fate in the mammalian embryo. Here the investigators propose to use embryonic stem cells (ESCs) as a platform for investigating these questions using a combination of live-cell imaging, quantitative analysis, and mathematical modeling. We will quantitatively characterize and model how BMP induces Wnt and then how Wnt induces Nodal, and how cell fate is a function of the dynamics of these multiple signals. They will then generate a synthesized model for how these three pathways control fate decisions. Due to the complexity of this problem, they will not attempt to model the gene regulatory network directly but will use landscape models, a mathematical formalization of the concept of the Waddington landscape in which a differentiating cell is envisioned as a ball rolling down a hill to valleys which represent stable cell fates. The investigators and others have recently had success in using this framework to quantitatively fit data and to make predictions about developmental systems, and here we will extend it and apply it to this key phase of development. They expect this to reveal the landscape in which cells make fate decisions, providing fundamental insight into this important problem as well as serving as a tool for predictive control over stem cell differentiation. 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.