Patterns and mechanisms of post-translational regulation of Mmp2 in vivo during zebrafish development

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University of New Brunswick


In addition to cells, multicellular tissues are made up of context-specific complexes of secreted proteins that are assembled dynamically outside cells to produce the physical characteristics of the vertebrate body and organs. The resistive strength of tendons, the elasticity and impermeability of skin and the support structure of the skeleton are functional largely because of the extracellular matrix (ECM). The development and maintenance of these tissues requires careful orchestration between assembly and degradation of components. Matrix metalloproteinases (MMPs) are one of the enzyme families known to degrade ECM. Matrix metalloproteinase-2 (MMP-2), my enzyme of interest, is known to have roles in pathologies such as arthritis, where its function is protective, and cancer metastasis, where it is activated as part of the migration and invasion of metastatic cells. It is an enzyme that requires post-translational activation by proteolytic cleavage, and therefore its role cannot be fully described by either mmp2 transcript patterns or Mmp2 protein accumulation. Using a transgenic zebrafish line with the epitope-mediated MMP activation (EMMA) assay construct, for the first time we can localize activation of Mmp2 in vivo, and here I describe its presence and activation during embryonic development. Though endogenous Mmp2 is expressed ubiquitously during the development of a zebrafish embryo, I show here that it is proteolytically activated in a much smaller set of structures. It is most strongly activated in the notochord, epithelium, fin folds and neural tube. Active Mmp2 has a role during the morphogenesis of the notochord, a driving structure in vertebrate development, and in the fin folds where actinotrichia are collagen based ECM structures that form the basis for fin rays. Further, I show that the activation mechanisms of Mmp2 are tissue- and stage-dependent: mechanisms that require metalloproteases are required for the activation of Mmp2 during fin fold development, but mechanisms dependent upon serine proteases are involved in the activation of Mmp2 in the notochord during notochord elongation and straightening. This is the first description of activation patterns in vivo and offers a starting point from which to examine the requirement of metalloproteases during development and to interrogate their mechanisms of activation.