Role of Membrane-Type Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinase-2 in Neural Crest Cell Migration

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Cantemir, Veronica
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During embryonic development, cardiac neural crest {NC) cells arise from the dorsal portion of the neural tube through an epithelial-to-mesenchymal transition and then migrate into the pharyngeal arches and subsequently participate in the septation of (he cardiac outflow tract and formation of the great vessels. Membrane-type matrix metalloproteinases (MT-MMPs) and their inhibitors are important in cell migration and cancer progression and metastasis. Previous studies have shown that cardiac NC cells migrate into MMP-2-containing ECM and cardiac NC cell migration is reduced but not eliminated using synthetic non-selective MMP inhibitors. Moreover, cardiac NC cells express tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and TIMP-2 is thought to be necessary for proMMP-2 activation by enabling the formation of a ternary complex with proMMP-2 and MT1-MMP. In addition to its MMP inhibitory activity, recent studies show that TIMP-2 has growth factor-like properties and can mediate growth factor signaling. Therefore, this thesis tested the hypothesis that cardiac NC cell formation and migration is dependent on cardiac NC cell expression of MT1-MMP and TIMP-2. Results of the experiments showed that there is a chicken homologue to MT1- MMP that shares high homology with other vertebrate MTl-MMPs. Cardiac NC progenitors and cardiac NC cells did not express detectable levels by in situ hybridization of sense MT1-MMP transcripts, rather, they express antisense MTI-MMP transcripts. While cardiac NC cells did not express detectable levels of other MT-MMPs. MT2-MMP expression was observed in the otic placodes, notochord, and dorsal part of the intermediate mesoderm (future nephric duct). Moreover, the RT-PCR experiments showed that MT5-MMP and an inhibitor of MT-MMPs, RECK, were expressed in the chicken embryos at stages of NC cell formation and migration, but were not detected in NC cells by in situ hybridization. Blocking TIMP-2 synthesis in cardiac NC cell progenitors using antisense morpholino oligonucleotides not only inhibited cardiac NC migration, but also caused embryonic growth restriction and increased embryonic mortality. Because non-selective MMP inhibitors have relatively minor effects on NC cell migration and because cardiac NC cells did not express detectable levels of sense mRNA for MT1-MMP, TIMP-2’s functional role in cardiac NC cell migration may not involve the formation of an MMP activation ternary complex with MT1-MMP. In conclusion, these results suggest that the previous notion of TIMP-2's primarily role as an MMP inhibitor or proMMP activator may not apply in the situation of chicken NC cell migration and embryonic development.
Creighton University
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