Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo

PLOS ONE, Nov 2019

Matrix metalloproteinases (MMPs) constitute a large group of endoproteases that play important functions during embryonic development, tumor metastasis and angiogenesis by degrading components of the extracellular matrix. Within this family, we focused our study on Mt4-mmp (also called Mmp17) that belongs to a distinct subset that is anchored to the cell surface via a glycosylphosphatidylinositol (GPI) moiety and with the catalytic site exposed to the extracellular space. Information about its function and substrates is very limited to date, and little has been reported on its role in the developing embryo. Here, we report a detailed expression analysis of Mt4-mmp during mouse embryonic development by using a LacZ reporter transgenic mouse line. We showed that Mt4-mmp is detected from early stages of development to postnatal stages following a dynamic and restricted pattern of expression. Mt4-mmp was first detected at E8.5 limited to the intersomitic vascularization, the endocardial endothelium and the dorsal aorta. Mt4-mmpLacZ/+ cells were also observed in the neural crest cells, somites, floor plate and notochord at early stages. From E10.5, expression localized in the limb buds and persists during limb development. A strong expression in the brain begins at E12.5 and continues to postnatal stages. Specifically, staining was observed in the olfactory bulb, cerebral cortex, hippocampus, striatum, septum, dorsal thalamus and the spinal cord. In addition, LacZ-positive cells were also detected during eye development, initially at the hyaloid artery and later on located in the lens and the neural retina. Mt4-mmp expression was confirmed by quantitative RT-PCR and western blot analysis in some embryonic tissues. Our data point to distinct functions for this metalloproteinase during embryonic development, particularly during brain formation, angiogenesis and limb development.

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Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo

September Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/ Mmp17) in the mouse embryo MarÂõa Jose Blanco 0 1 Iva n RodrÂõguez-MartÂõn 0 1 Ana I. R. Learte 0 1 Cristina Clemente 1 MarÂõa Gregoria Montalvo 1 Motoharu Seiki 1 2 Alicia G. Arroyo 1 Cristina Sa nchez- Camacho 1 0 Basic Biomedical Sciences Department, Universidad Europea de Madrid, Villaviciosa de OdoÂn , Madrid , Spain , 2 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , Madrid , Spain , 3 Doctoral Studies and Research School, Universidad Europea de Madrid, Villaviciosa de Od oÂn , Madrid , Spain 1 Editor: Michael Schubert, Laboratoire de Biologie du DeÂveloppement de Villefranche-sur-Mer , FRANCE 2 Institute of Medical Science, University of Tokyo , Minato-ku, Tokyo , Japan Matrix metalloproteinases (MMPs) constitute a large group of endoproteases that play important functions during embryonic development, tumor metastasis and angiogenesis by degrading components of the extracellular matrix. Within this family, we focused our study on Mt4-mmp (also called Mmp17) that belongs to a distinct subset that is anchored to the cell surface via a glycosylphosphatidylinositol (GPI) moiety and with the catalytic site exposed to the extracellular space. Information about its function and substrates is very limited to date, and little has been reported on its role in the developing embryo. Here, we report a detailed expression analysis of Mt4-mmp during mouse embryonic development by using a LacZ reporter transgenic mouse line. We showed that Mt4-mmp is detected from early stages of development to postnatal stages following a dynamic and restricted pattern of expression. Mt4-mmp was first detected at E8.5 limited to the intersomitic vascularization, the endocardial endothelium and the dorsal aorta. Mt4-mmpLacZ/+ cells were also observed in the neural crest cells, somites, floor plate and notochord at early stages. From E10.5, expression localized in the limb buds and persists during limb development. A strong expression in the brain begins at E12.5 and continues to postnatal stages. Specifically, staining was observed in the olfactory bulb, cerebral cortex, hippocampus, striatum, septum, dorsal thalamus and the spinal cord. In addition, LacZ-positive cells were also detected during eye development, initially at the hyaloid artery and later on located in the lens and the neural retina. Mt4-mmp expression was confirmed by quantitative RT-PCR and western blot analysis in some embryonic tissues. Our data point to distinct functions for this metalloproteinase during embryonic development, particularly during brain formation, angiogenesis - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by a grant from the Universidad Europea de Madrid (2016UEM04) to C.S.C. and grant SAF2014-20520R from the Ministry of Economy, Industry and Competitiveness (MIEC) to A.G.A. The CNIC is supported by the MIEC and the Pro-CNIC and limb development. Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Introduction Matrix metalloproteinases (MMPs) constitute a large group of endoproteases that are mainly aimed to degrade and modify distinct components of the extracellular matrix (ECM). These enzymes play also a key role as regulators for tumor invasion and vascular formation [ 1 ]. The MMPs are mostly secreted, although there is a subgroup that are tethered to the cell membrane (MT-MMPs), either by a single transmembrane domain or by a glycophosphatidyl inositol (GPI) anchor, and with the catalytic site exposed to the extracellular space [ 2,3 ]. The membrane anchored MT-MMPs are relevant modifiers of the immediate cellular microenvironment, which modulates cellular functions [4]. This subgroup includes Mt4-mmp, also known as Mmp17, which is a relatively new member of the MMP family and has been poorly characterized to date [ 5,6 ]. Mt4-mmp exhibits unique structural and functional characteristics since it has the least degree of sequence identity to the other family members, presenting no shared enzymatic properties with them [ 1,7 ]. For instance, its proteolytic activity against ECM proteins is limited, suggesting a certain degree of specificity against its substrates, possibly located in the pericellular space as well as in the plasma membrane associated to lipid rafts [ 5,6,8 ]. Mt4-mmp physiological role remains unclear: its loss of function seems to trigger no apparent defects in gestation, growth, morphology, fertility and behavior, and mice showed no apparent abnormal developmental phenotypes [ 9 ]. However, it is known that Mt4-mmp is highly expressed in the kidney papilla as well as in the anterior hypothalamus, and null mice have decreased intake of water and daily urine output, suggesting a role for this enzyme in water homeostasis and regulation of the thirst center in mice [ 10 ]. Th (...truncated)


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María José Blanco, Iván Rodríguez-Martín, Ana I. R. Learte, Cristina Clemente, María Gregoria Montalvo, Motoharu Seiki, Alicia G. Arroyo, Cristina Sánchez-Camacho. Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo, PLOS ONE, 2017, Volume 12, Issue 9, DOI: 10.1371/journal.pone.0184767