Investigating cellular plasticity in the avian primitive streak

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THE 'BIG' PICTURE: A fascinating question in biology asks how multicellular organisms arise from a single cell: the fertilized egg. During embryogenesis naïve and still plastic progenitor cells interact with each other, first to form different embryonic layers and to organize the main body axes, and later to build specialized organs with highly differentiated cell types and functions. The cells in an embryo coordinate these complex events by communicating with each other using molecular signalling mechanisms. Cell-cell communication is important throughout the life of an organism, for example for repair after injury or for growth and remodelling. A good example for this is skeletal muscle, a tissue that can regenerate and rebuild itself (after injury or after exercise). This is possible, because there are specialized cells in muscle, but also in other tissues, which can divide when stimulated and make more differentiated cells when needed. These specialized cells are tissue-resident stem cells and they respond to the same communication signals that act in the embryo. We need to understand the detailed intricacies of these signals, as they can have different effects depending on the context in which they act. Defects in signalling mechanisms can be detrimental to an embryo, but they can also lead to diseases in adults such as cancer, when cells "mis-behave" and ignore the signals or respond incorrectly and grow uncontrollably as a result.EXPERIMENTAL MODEL SYSTEM: We have used the early chick embryo, which is very similar in its morphology to early human embryos, and investigated the effects of two important cell-cell signaling pathways. From these studies we know that BMP and WNT signals have different effects in different types of early progenitor cells, depending on the stage of development. We also know that these pathways act via a common transcriptional regulator (SMAD), which can switch other genes 'on' or 'off'. In a "HH stage 3" embryo the signals change how cells migrate, but in a "HH stage 4" embryo the SAME signals have no effect on migration but instead alter the fate of the cells; thus at this later stage the cells respond by changing what they will become. We will use state-of-the-art molecular protocols to identify the genes that are switched on or off by the SMAD-switch in these cell populations. We have experience with these methods in the chick embryo, an accessible experimental system and we have assembled a highly skilled team of researchers to execute this programme of research.WHY IS THIS IMPORTANT? BMP and Wnt signaling are widely used cell communication signals that act in many tissues and organs. We know many of the components of the pathways, but we still do not understand why cellular responses to the (apparently) same trigger vary depending on the context. We now have a well-defined system where the cellular response to the same signals has been characterized and is quite divergent: EITHER cell migration is affected OR cell specification is affected. This gives us the unique opportunity to identify which genes have been switched on or off in the responding cells and provide a deeper mechanistic insight at the molecular level. This is needed in order to fully understand how specialised cells form and how they build functional organs. This is not only relevant in developing embryos, if things go wrong the embryo will not survive or become malformed, but is also relevant for stem cell science and tissue engineering, emerging fields of increasing importance and with significant future potential for medicine and health.SPECIFIC OBJECTIVES: We will capitalize on our recent observations and use our well established model system to (1) identify genes that are differentially expressed in response to BMP and Wnt signaling, and to (2) test the expression and function of these genes in both cell migration and cell specification/differentiation.