Dynamic Expression of Membrane Type 1-Matrix Metalloproteinase (Mt1-mmp/Mmp14) in the Mouse Embryo

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.

Emerging roles ofMT‐MMPsin embryonic development

“…[65][66][67][68][69][70] Notably, a recent study identifies a dynamic expression pattern for MT1-MMPin the mouse embryo, particularly in the developing cardiovascular and nervous systems and the limbs. 71 These results support that MT1-MMP may participate in distinct morphogenetic processes during embryogenesis that requires cell migration. Indeed, MT1-MMP expression has been reported in the olfactory bulb at early embryonic stages.…”

“…Indeed, MT1-MMP expression has been reported in the olfactory bulb at early embryonic stages. 71 Supporting these data, MT1-MMP as well as MT2-, MT3-, MT4-and MT5-MMP are all expressed in the subventricular zone, the rostral migratory stream, and the olfactory bulb at postnatal stages and persists in the adulthood 72 (Table 2). In fact, neuroblast migration is reduced by MMP inhibitors and the migrating olfactory stem cells show MT1-MMP-enriched lamellipodia [72][73][74] (Table 2).…”

“…This is in line with the reported expression of MT1-MMP in the mouse embryonic heart where the enzyme was found in the primitive atrium, the ventricle, the cardiac outflow tract, and the endothelial cells of the endocardium. 71 Interestingly, this expression pattern persists along heart morphogenesis supporting the requirement of this transmembrane MMP during cardiac development. 71 Similarly, MT2-MMP, through a direct transactivation by Snai1, has been also involved in endocardial cushion development.…”

“…MT1-MMP is also expressed in embryonic connective tissue cells such as osteoblasts, osteoclasts, and perichondrial, muscle, and tendon fibroblasts. 67,71,81,82 During osteogenesis, differentiation of skeletal stem cells is regulated by MT1-MMP/β1 integrin/YAP/TAZ signaling axis 83 (Table 2). In fact, Mt1-mmp À/À mice display several craniofacial abnormalities as well as skeletal tissue disorders 84,85 (Table 2).…”

“…134 Supporting these data, the enzyme is also reported in the migrating NCCs along the neural tube in the mouse embryo. 71 Additionally, MT1-MMP is required for basal positioning of NCC nuclei prior to epithelial delamination during the formation of the chicken neural tube. This novel function is proposed to be relevant for the regulation of EMT during development independently of its catalytic activity, suggesting that it may play an important role in the accomplishment of epithelial basal cell extrusions through mechanisms yet to be explored 135 (Table 2).…”