MMP activation during xenopus development

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Animals have evolved numerous ways to grow from a fertilized egg to a reproductive adult. Many developmental strategies and approaches are used, but there are several constants. Among these constants is the need for cell-to-cell communication and interactions. These interactions allow for important signalling events to occur at the correct time and place during development. Interestingly these events in part are regulated by proteins found outside of cells - the extracellular matrix (ECM). The ECM has been recognized for decades, but it is only recently that its importance is clearly understood. The ECM can influence how cells communicate with each other, and so the degradation or remodelling of the ECM will affect this cell-cell communication. These changes and remodelling of the ECM have been observed in diseases such as cancer where secreted enzymes (matrix metalloproteinases, MMPs) were identified that changed the ECM. MMPs are now known to play important roles in development, where they appropriately regulate the structure of the ECM. As MMPs can have profound impacts, their activity is regulated in a number of ways. Most MMPs are secreted outside of cells in an inactive form and are activated when needed. MMPs are often activated by other cell-surface MMPs called MT-MMPs. Intriguingly (and counter intuitively) MT-MMPs work with secreted inhibitors, TIMPs (their inhibitors) to activate other MMPs. This activation process is delicately balanced as an excess of TIMP molecules would inhibit all MT-MMPs and thus stop the activation process. MMPs, MT-MMP and TIMPs individually have important developmental functions. However, very little is known about how they interact with each other to appropriately regulate the remodelling of the ECM during development.  This research proposal uses frog as a developmental model with which the functions and interactions of these molecules can be assayed. By understanding their role and how they act during the development of a living organism we can then better understand the underlying mechanisms that play a role in normal and abnormal embryogenesis.