CAREER: Mechanisms Underlying Temporal Integration of BMP Signaling in Cell Fate Decisions

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

The Heemskerk lab previously showed that for the cell signal called Bone Morphogenetic Protein (BMP), cells add up the amount of signal they see over time to decide whether to specialize to one specific cell type. This project will combine experimental and computational methods to understand how cells keep track of the past signaling and determine if later specialization events to other cell types follow the same rules. Multiple undergraduate and graduate students will be trained to perform this research, preparing them for careers that increasingly demand integration of computational and experimental approaches to tackle scientific problems. A collaboration with the University of Michigan Museum of Natural History (UMMNH) will communicate stem cell research and its societal benefits to audiences. To reach younger audiences, the researchers will partner with the UMMNH to develop a curriculum for teaching middle school students from metro-Detroit, as well as a small year-long exhibit and additional outreach activities at the museum. To reach adults, the research team will discuss stem cell research and human development in public Science Café events and expand a course module for graduate students to teach the methods applied in this project. BMP is a quintessential signaling molecule that plays a conserved role in early development. This project uses human pluripotent stem cells (hPSCs) as an in vitro model to address the mechanisms by which BMP controls cell fate decisions in early human development. Preliminary work revealed that differentiation of hPSCs to amnion-like cells does not depend on the level or duration of signaling separately, but only on the time integral, i.e. the total amount of signaling over time. This is contrary to the common assumption that signaling level is the main determinant of cell response and implies different molecular mechanisms for signal processing. A preliminary screen yielded genes whose levels are linearly related to the time integral of signaling, providing a simple potential mechanism, but how these genes are regulated by BMP and how they in turn control other genes is unclear. We also do not know if BMP integration is conserved across different contexts. Therefore, this project aims to 1) reveal the mechanisms underlying temporal integration of BMP signaling during amnion-like differentiation, 2) understand how signal response depends on the initial state of the cell, 3) determine if these mechanisms are conserved across different cell fate decisions and species. Together, this work will yield a more profound understanding of BMP signaling in pluripotent stem cells and contribute to revealing general principles by which dynamic signaling controls cell fate, enabling more reproducible stem cell differentiation in vitro. 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.