Blastocyst-dependent upregulation of metalloproteinase/disintegrin MDC9 expression in rabbit endometrium

Olson, Gary E.; Winfrey, Virginia P.; Matrisian, P E; NagDas, Subir K.; Hoffman, Loren H.

doi:10.1007/s004410051141

Cited by 45 publications

(27 citation statements)

References 39 publications

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“…Previous findings in rabbits indicate a hormonally and blastocyst-dependent increase in ADAM 9 expression and MUC1 loss at regions of cell-cell adhesion and fusion in the uterus during implantation (32), suggesting a crucial role for ADAM 9 in this species. Clearance of MUC1 from the surface of human uterine epithelial cells also appears to be a necessary prerequisite for the creation of an environment conducive to blastocyst attachment.…”

Section: Fig 4 Muc1 Shedding Does Not Occur In Tacementioning

confidence: 75%

“…However, the presence of the blastocyst in the rabbit endometrium results in a localized reduction of MUC1 at the site of implantation (30,31). Coincidentally, ADAM 9 accumulates at sites of blastocyst attachment (and MUC1 loss) (32), implicating a role for this ADAM in the implantation process in rabbits. An in vitro study of cultured human uterine epithelial cells similarly demonstrated a local loss of MUC1 at the site of human blastocyst attachment (33).…”

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confidence: 99%

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Tumor Necrosis Factor-α Converting Enzyme/ADAM 17 Mediates MUC1 Shedding

Thathiah

Blobel

Carson

2003

Journal of Biological Chemistry

183

139

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MUC1 clearance from the uterine epithelial cell surface is a prerequisite for the creation of an environment conducive to embryo implantation. In some species, reduced mRNA levels along with metabolic turnover account for loss of MUC1 during the receptive phase throughout the uterine epithelium. In other species, MUC1 is rapidly lost solely at the site of blastocyst attachment, suggesting the action of a protease. Correlative studies also indicate the presence of soluble forms of MUC1 in cell culture supernatants in vitro and in bodily fluids in vivo. To characterize the proteolytic activity mediating MUC1 release, shedding of MUC1 was analyzed in a human uterine epithelial cell line (HES) that abundantly expresses and readily sheds MUC1. MUC1 release was stimulated by phorbol 12-myristate 13-acetate and was markedly inhibited by the synthetic peptide hydroxamate metalloprotease inhibitor, tumor necrosis factor-␣ protease inhibitor (TAPI), as well as by an endogenous inhibitor of matrix metalloproteases, tissue inhibitor of metalloproteases (TIMP)-3. These characteristics along with studies conducted with cell lines genetically deficient in various ADAMs (for a disintegrin and metalloprotease) identified tumor necrosis factor-␣ converting enzyme (TACE)/ADAM 17 as a MUC1 sheddase. Furthermore, both TACE and MUC1 were expressed in human uterine epithelia during the receptive phase, and co-immunoprecipitation experiments revealed a physical interaction between TACE and MUC1 in HES cells. These studies establish a proteolytic mechanism for MUC1 clearance from a human uterine epithelial cell line and identify TACE as a MUC1 sheddase.

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Section: Fig 4 Muc1 Shedding Does Not Occur In Tacementioning

confidence: 75%

mentioning

confidence: 99%

Tumor Necrosis Factor-α Converting Enzyme/ADAM 17 Mediates MUC1 Shedding

Thathiah

Blobel

Carson

2003

Journal of Biological Chemistry

183

139

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“…No major morphological changes or histopathological defects during development or in the adult were evident in mdc9 Ϫ/Ϫ mice compared to wild-type control animals. mdc9 Ϫ/Ϫ mice are fertile and do not have a significant difference in litter size compared to wild-type controls, arguing against an essential role for MDC9 in blastocyst implantation (33). The lack of any apparent developmental defect or severe pathological phenotype in mdc9 Ϫ/Ϫ mice, despite the ubiquitous expression of this protein during development and in the adult, could result from functional compensation by or redundancy with other members of the ADAM family or perhaps even other molecules.…”

Section: Discussionmentioning

confidence: 99%

“…MDC9 is highly conserved between mouse, human, and Xenopus, suggesting a conserved role in most or all cells and tissues (8). MDC9 is highly ex-pressed at the blastocyst implantation site in the uterus in rabbits, suggesting a possible role in implantation (33). Biochemical studies have shown that recombinant MDC9 has a different peptide cleavage specificity and inhibitor profile from those of TACE, suggesting that MDC9 has different substrates in cells (39).…”

mentioning

confidence: 99%

Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life

Weskamp¹,

Cai²,

Brodie

et al. 2002

Molecular and Cellular Biology

189

147

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MDC9 (ADAM9/meltrin ␥) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an ␣ secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9 ؊/؊ mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9 ؊/؊ mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9 ؊/؊ and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP ␣ and ␥ secretase cleavage product (p3) and of ␤-and ␥-secretase cleavage product (A␤) in cultured hippocampal neurons from mdc9 ؊/؊ or wild-type mice, arguing against an essential major role of MDC9 as an ␣-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.Metalloprotease-disintegrins (ADAMs) are a family of membrane-anchored glycoproteins that have been implicated in fertilization, myogenesis, neurogenesis, and protein ectodomain shedding (for recent reviews, see references 3, 36, and 42). The first recognized ADAMs were the ␣ and ␤ subunits of the sperm protein fertilin, a protein with an essential role in fertilization (5,10,35). Since the discovery of fertilin, a total of 33 ADAMs have been identified in a variety of organisms, 24 of which are found in the mouse (see the following URLs for details: www.people.Virginia.EDU/ϳjag6n/adams.html and www.uta.fi/ϳloiika/HADAMs.htm). About half of these proteins have a catalytic-site consensus sequence (HEXXH) in their metalloprotease domain and are predicted to be catalytically active. The remaining ADAMs do not have a catalytic site in their metalloprotease domain and are therefore not predicted to be catalytically active, even though the domain is otherwise quite highly conserved. ADAMs are also thought to have roles in cell-cell adhesion, for example through interactions with integrins (9, 12, 31) or syndecans (17).Despite the substantial number of ADAMs that have been identified to date, only a few have known biological functions. Mice lacking functional ADAM17/TACE die shortly after birth, apparently as a result of a defect in protein ectodomain shedding of epidermal growth factor (EGF) receptor ligands such as transforming growth factor ␣...

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“…In Situ Hybridization-Sense and antisense riboprobes for nonisotopic in situ hybridization (26,27) were prepared using 1 g of linearized plasmid in 20-l transcription reactions containing 40 -50 units of SP6 (Promega, Madison, WI) or T7 (New England Biolabs, Waverly, MA) polymerase, 1ϫ transcription buffer, 20 units of RNase inhibitor, 1 mM each of ATP, CTP, GTP, 0.65 mM UTP, and 0.35 mM Dig-UTP (Roche Applied Science). Unincorporated nucleotides were removed with a Chroma Spin-100 STE column (Clontech, Palo Alto, CA), and probes were stored at Ϫ75°C.…”

Section: Methodsmentioning

confidence: 99%

Region-specific Expression and Secretion of the Fibrinogen-related Protein, fgl2, by Epithelial Cells of the Hamster Epididymis and Its Role in Disposal of Defective Spermatozoa

Olson

Winfrey

NagDas

et al. 2004

Journal of Biological Chemistry

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The cauda epididymidis functions in the storage and protection of mature, fertile spermatozoa. We previously identified a region-specific secretory glycoprotein (termed HEP64) of the hamster proximal cauda epididymidis that specifically bound and coated the nonviable, but not the viable, spermatozoa within the epididymal lumen. In this study we employed expression screening of a hamster epididymal cDNA library to obtain the full-length sequence of HEP64 and to identify it as the fibrinogen-like protein fgl2. Northern blot analysis demonstrated that fgl2 mRNA is highly expressed by the proximal cauda epididymidis in comparison to other hamster tissues examined, and, in situ hybridization analysis of the epididymis revealed that fgl2 mRNA exhibited a region-and principal cell-specific expression pattern. Immunohistochemistry confirmed the association of fgl2 with abnormal spermatozoa in the cauda epididymidis and revealed smaller fgl2-containing particles. Immunoelectron microscopy revealed that fgl2 was distributed throughout an amorphous, "death cocoon," complex assembled onto abnormal spermatozoa and that the smaller fgl2 aggregates consisted of the amorphous material with embedded sperm fragments, organelles, and membrane vesicles. A protocol was developed to isolate an enriched death cocoon fraction. SDS-PAGE and microsequence analyses revealed that the M r 64,000 fgl2 monomer was assembled into two disulfide-linked oligomers of M r 260,000 and 280,000. These data demonstrate that the epididymis possesses a specific mechanism to identify and envelop defective spermatozoa with a protein complex containing the fibrinogen-like protein fgl2. We propose that this represents an important protective mechanism not only to shield the viable sperm population from potentially deleterious enzymes released by dying spermatozoa but also to prevent the release of sperm proteins that could initiate an immune response if they escaped the epididymal environment.Mammalian spermatozoa exiting the testis are functionally immature and must undergo a series of developmental modifications in the epididymis to acquire forward motility and fertilizing capacity (1, 2). In the species studied, spermatozoa from the proximal cauda epididymidis exhibit fertilizing capacity, and the distal cauda functions as a storage reservoir that maintains the viability of mature spermatozoa (1, 3). Both the sperm maturation and storage functions of the epididymis depend upon paracrine interactions between the epididymal epithelium and spermatozoa, which are mediated by a progressively modulated luminal fluid environment of region-specific ionic, organic solute, and protein composition (4, 5). The luminal fluid is produced by the secretory and absorptive activities of a lining epithelium whose major cell type, the principal cell, also displays striking regional differences in its gene expression and protein secretion patterns (6). Several principal cell secretory proteins appear to modify the sperm plasma membrane and promote their maturation (7,8). Howe...

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Blastocyst-dependent upregulation of metalloproteinase/disintegrin MDC9 expression in rabbit endometrium

Cited by 45 publications

References 39 publications

Tumor Necrosis Factor-α Converting Enzyme/ADAM 17 Mediates MUC1 Shedding

Tumor Necrosis Factor-α Converting Enzyme/ADAM 17 Mediates MUC1 Shedding

Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life

Region-specific Expression and Secretion of the Fibrinogen-related Protein, fgl2, by Epithelial Cells of the Hamster Epididymis and Its Role in Disposal of Defective Spermatozoa

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