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
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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)