Abstract
MT1-MMP/MMP14 belongs to a subgroup of the matrix metalloproteinases family that presents a transmembrane domain, with a cytosolic tail and the catalytic site exposed to the extracellular space. Deficient mice for this enzyme result in early postnatal death and display severe defects in skeletal, muscle and lung development. By using a transgenic line expressing the LacZ reporter under the control of the endogenous Mt1-mmp promoter, we reported a dynamic spatiotemporal expression pattern for Mt1-mmp from early embryonic to perinatal stages during cardiovascular development and brain formation. Thus, Mt1-mmp shows expression in the endocardium of the heart and the truncus arteriosus by E8.5, and is also strongly detected during vascular system development as well as in endothelial cells. In the brain, LacZ reporter expression was detected in the olfactory bulb, the rostral cerebral cortex and the caudal mesencephalic tectum. LacZ-positive cells were observed in neural progenitors of the spinal cord, neural crest cells and the intersomitic region. In the limb, Mt1-mmp expression was restricted to blood vessels, cartilage primordium and muscles. Detection of the enzyme was confirmed by Western blot and immunohistochemical analysis. We suggest novel functions for this metalloproteinase in angiogenesis, endocardial formation and vascularization during organogenesis. Moreover, Mt1-mmp expression revealed that the enzyme may contribute to heart, muscle and brain throughout development.
Highlights
Introductionmatrix metalloproteinases (MMPs) are divided into soluble MMPs, secreted into the extracellular milieu by cells including fibroblasts, vascular smooth muscle cells (VSMC) and leukocytes among others, or expressed on the cell surface as a membranetethered form: membrane type-MMPs (MT-MMPs) [2,4]
Only few reports have claimed that MT1-matrix metalloproteinases (MMPs) may play a role during embryonic angiogenesis according to the vascular defects observed during lung morphogenesis or vascular invasion of cartilage [13,14,53]
Based on our results about MT1-MMP expression in endothelial cells of distinct embryonic tissues, we suggest that the metalloproteinase may be relevant for vascularization during organogenesis in the embryo as well as during heart development
Summary
MMPs are divided into soluble MMPs, secreted into the extracellular milieu by cells including fibroblasts, vascular smooth muscle cells (VSMC) and leukocytes among others, or expressed on the cell surface as a membranetethered form: membrane type-MMPs (MT-MMPs) [2,4]. The furin recognizes a sequence (RRKR111 ) located at the C-terminal end of the pro-domain and cleaves it for activation This leads to the mature form of the enzyme, which later is expressed on the cell surface [1,2,3,5]. Regulation of its activity relies on its endogenous inhibition through, amongst others, TIMP-2 and the tumor suppressor RECK [3,5,8]
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