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 creating the patterns which are the template for the formation of functioning organs. In this project which is a collaboration between researchers at the California Institute of Technology (US) and the Francis Crick Institute (UK), investigators will use a novel quantitative approach to examine signaling in the Sonic Hedgehog pathway (a signaling pathway very important in development) at the single cell level that leads to neural patterning in a model tissue culture system. The results will elucidate the mechanism that controls the precision of cell fate decision and tissue patterning in the developing spinal cord. These broader impacts of these principles are likely to be relevant for understanding other signaling pathways involved in diverse developmental processes. This project will also provide a unique opportunity for training graduate students at the interface of biology and computation.
During embryonic development and in response to injury, tissues must establish, or re-establish, precise spatial arrangements of specific cell types. A common strategy of tissue patterning involves morphogens; locally produced, secreted molecules that diffuse to form concentration gradients. These gradients provide the tissue with positional information that is used to regulate spatially specific genes controlling cell fate decisions. Moreover, morphogens also regulate the downstream target genes that can affect the morphogen movement, intracellular signal transduction and the elaboration of target gene expression. This provides a means for morphogens to generate gradients and positional information with context-specific shapes and dynamics to instruct tissue pattern formation. A key limitation in understanding the architecture of pathways that control morphogen expression has been the lack of direct readout and control in embryonic tissues. To address this deficiency, this research project will combine novel quantitative single- cell and tissue engineering approaches in well-defined cellular model systems. The aim of this project is to understand the design principles that produce the dynamics and gene responses of the Hedgehog (SHH) pathway, which are involved in diverse developmental processes, in particular patterning the neural system. The following fundamental questions about morphogen-mediated tissue patterning will be addressed: (1) How are the dynamics of morphogen gradients generated and controlled? (2) How do the genes in individual cells interpret the quantitative, dynamic information encoded by morphogens into discrete cell fates? (3) How do fluctuations, or "noise", limit the precision of patterning, and how do cells overcome these limitations? A broader impact of this project will be predictive, quantitative models connecting morphogen dynamics to cell fate decision-making, which provides insights into numerous Shh-dependent processes in embryos and organisms, and also enables researchers to control and repurpose Shh signaling in order to engineer patterning in manufactured tissues. This project will also provide a unique opportunity for training graduate students at the interface of biology and computation.
This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.
