Bilateral NSF/BIO-BBSRC: The design logic of Hedgehog-based pattern formation

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A key challenge in biology is to understand how cells communicate and respond to one another. This is particularly important in developing embryos where cell communication is responsible for organizing tissues and creating the patterns of cell types that are the template for the formation of functioning organs. Over the last few decades rapid progress has been made in identifying the genes and so-called 'signaling pathways' involved in tissue development. However we have relatively little knowledge of the design logic and dynamics of these pathways, and usually limited ability to perturb or control these pathways in a predictable way. How do these pathways work, and what capabilities do they provide? And, how can we predict their response to perturbations or use them to control cellular behaviors? To achieve a more fundamental understanding of these issues requires a shift in approach from a qualitative molecular view to a quantitative systems analysis. Gaining insight is necessary in order to understand, for instance, how precision and reproducibility of developmental patterning is achieved and ultimately in order to understand how to control these processes when they go wrong or to engineer new tissues.In this proposal we aim to understand the design principles that produce the dynamics and gene responses of the Hedgehog pathway. This pathway provides an experimentally tractable example of a developmentally important signaling pathway involved in diverse developmental processes and pathologies. However, although we know a lot about the proteins, interactions and feedback loops in the pathway we have little understanding of why the pathway has this architecture, how it behaves dynamically in an individual cell, and how its dynamics ensure proper tissue development. A key limitation has been the lack of direct readout and control of pathway activity at the level of individual cells, and the ability to link these data to tissue level assays. To address this deficiency we plan to combine the expertise of our labs and use a combination of quantitative single-cell and developmental biology approaches in well-defined cellular model systems. The Elowitz lab has expertise in developing and analyzing single cell quantitative data from a range of biological systems; whereas the Briscoe lab has experience and reagents to analyse Hedgehog signaling in neural tissue, where it is responsible for generating different neuronal subtypes. The project will develop reagents and methods that provide a new quantitative understanding of the Hedgehog pathway. Obtaining this systems level of view of the pathway will provide insight into how signals are communicated in developing tissues and reveal what features of the Shh pathway support this. These design principles are likely to be relevant for understanding not only Hedgehog but other signaling pathways involved in diverse developmental processes. More generally, introducing insights from quantitative and system biology to developmental and stem cell biology will advance the field and help underpin its future use in drug discovery, preclinical models of disease, and ultimately clinical applications.