Multifunctional morphogens: patterning precision and mesoderm migration

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

PROJECT SUMMARY Across development, a relatively small set of cell signaling pathways simultaneously controls many cell behaviors including proliferation, differentiation, and migration. How cells process signaling information to perform multiple functions and what limits their precision remains poorly understood. Complex pathway interactions generate dynamic signaling patterns that are difficult to disentangle in vivo. Moreover, many details of these interactions are species specific so that findings in model organisms cannot be simply translated to human. Our overall goal is to uncover how combinatorial cell signaling dynamics orchestrate development and determine what limits their precision. Our approach combines application of experimental and theoretical methods to stem cell models of human development. We previously created an experimental and computational pipeline to track cell signaling history and link it to fate in individual cells. We also developed an iterative staining method to take snapshots of many signals and fate markers simultaneously, and a theoretical framework to interpret this data. Moreover, we implemented a range of tools to study FGF signaling in human pluripotent stem cells. Finally, we established a highly reproducible model for human mesoderm migration. We used these methodological advances to provide new insight into both fundamental aspects of developmental signaling and specifics of human development. For example, we showed it is the total (BMP) signaling over time that controls differentiation to amnion-like cells, not the absolute level or duration as was previously thought. We also discovered how the relative timing of signals controls differentiation of primordial germ cell-like cells, which are of great interest for understanding and treating infertility, and we leveraged our insights to double the efficiency with which these can be derived in vitro. Building on our previous work, here we propose to address two unresolved questions: 1) How does cell signaling history control the precision of final cell fate and signaling patterns? 2) Which cues guide human mesoderm migration and how are they linked to fate? Defects in differentiation and migration during early development are linked to congenital birth defects and infertility, while imprecision of in vitro development limits applications of stem cell technology. This research will advance our understanding of cell signaling in developmental biology and disease with applications to stem cell technology.