Dual source and target of heparin-binding EGF-like growth factor during the onset of implantation in the hamster

Development ◽  
2002 ◽  
Vol 129 (17) ◽  
pp. 4125-4134
Author(s):  
Xiaohong Wang ◽  
Haibin Wang ◽  
Hiromichi Matsumoto ◽  
Shyamal K. Roy ◽  
Sanjoy K. Das ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nuclear Receptor ◽  
Similar Pattern ◽  
Implantation Site ◽  
Luminal Epithelium ◽  
Molecular Signaling ◽  
Heparin Binding ◽  
Important Mediator ◽  
Dual Source ◽  
Blastocyst Implantation

Heparin binding EGF-like growth factor (HB-EGF), encoded by the Hegfl gene, is considered as an important mediator of embryo-uterine interactions during implantation in mice. However, it is unknown whether HB-EGF is important for implantation in species with different steroid hormonal requirements. In mice and rats, maternal ovarian estrogen and progesterone (P4) are essential to implantation. In contrast, blastocyst implantation can occur in hamsters in the presence of P4 alone. To ascertain whether HB-EGF plays any role in implantation in hamsters, we examined the expression, regulation and signaling of HB-EGF in the hamster embryo and uterus during the periimplantation period. We demonstrate that both the blastocyst and uterus express HB-EGF during implantation. Hegfl is expressed solely in the uterine luminal epithelium surrounding the blastocyst prior to and during the initiation of implantation. Hypophysectomized P4-treated pregnant hamsters also showed a similar pattern of implantation-specific Hegfl expression. These results suggest that uterine Hegfl expression at the implantation site is driven by either signals emanating from the blastocyst or maternal P4, but not by maternal estrogen. However, in ovariectomized hamsters, uterine induction of Hegfl requires the presence of estrogen and activation of its nuclear receptor (ER), but not P4. This observation suggests an intriguing possibility that an estrogenic or unidentified signal from the blastocyst is the trigger for uterine HB-EGF expression. An auto-induction of Hegfl in the uterus by blastocyst-derived HB-EGF is also a possibility. We further observed that HB-EGF induces autophosphorylation of ErbB1 and ErbB4 in the uterus and blastocyst. Taken together, we propose that HB-EGF production and signaling by the blastocyst and uterus orchestrate the ‘two-way’ molecular signaling to initiate the process of implantation in hamsters.

Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1997-2005 ◽  
Author(s):  
B.C. Paria ◽  
K. Elenius ◽  
M. Klagsbrun ◽  
S.K. Dey
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Heparan Sulfate Proteoglycans ◽  
Receptor Expression ◽  
Luminal Epithelium ◽  
Apical Surface ◽  
Heparin Binding ◽  
High Affinity ◽  
Blastocyst Implantation

Blastocyst implantation requires molecular and cellular interactions between the uterine luminal epithelium and blastocyst trophectoderm. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is induced in the mouse luminal epithelium solely at the site of blastocyst apposition at 16:00 hours on day 4 of pregnancy prior to the attachment reaction (22:00-23:00 hours), and that HB-EGF promotes blastocyst growth, zona-hatching and trophoblast outgrowth. To delineate which EGF receptors participate in blastocyst activation, the toxicity of chimeric toxins composed of HB-EGF or TGF-(α) coupled to Pseudomonas exotoxin (PE) were used as measures of receptor expression. TGF-(α) or HB-EGF binds to EGF-receptor (ErbB1), while HB-EGF, in addition, binds to ErbB4. The results indicate that ErbB1 is inefficient in mediating TGF-(α)-PE or HB-EGF-PE toxicity as follows: (i) TGF-(α)-PE was relatively inferior in killing blastocysts, 100-fold less than HB-EGF-PE, (ii) analysis of blastocysts isolated from cross-bred egfr+/− mice demonstrated that HB-EGF-PE, but not TGF-(α)-PE, killed egfr−/− blastocysts, and (iii) blastocysts that survived TGF-(α)-PE were nevertheless killed by HB-EGF-PE. HB-EGF-PE toxicity was partially mediated by cell surface heparan sulfate proteoglycans (HSPG), since a peptide corresponding to the heparin-binding domain of HB-EGF as well as heparitinase treatment protected the blastocysts from the toxic effects of HB-EGF-PE by about 40%. ErbB4 is a candidate for being an HB-EGF-responsive receptor since RT-PCR analysis demonstrated that day 4 mouse blastocysts express two different erbB4 isoforms and immunostaining with anti-ErbB4 antibodies confirmed that ErbB4 protein is expressed at the apical surface of the trophectoderm cells. It is concluded that (i) HB-EGF interacts with the blastocyst cell surface via high-affinity receptors other than ErbB1, (ii) the HB-EGF interaction with high-affinity blastocysts receptors is regulated by heparan sulfate, and (iii) ErbB4 is a candidate for being a high-affinity receptor for HB-EGF on the surface of implantation-competent blastocysts.

Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 637-645 ◽  
Author(s):  
G. Raab ◽  
K. Kover ◽  
B.C. Paria ◽  
S.K. Dey ◽  
R.M. Ezzell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Transmembrane Protein ◽  
Mouse Cell ◽  
Cell Contact ◽  
Luminal Epithelium ◽  
Heparin Binding ◽  
Heparin Binding Domain ◽  
Epidermal Growth ◽  
Adhesion Factor

Previous studies have shown that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) mRNA is synthesized in the mouse uterine luminal epithelium temporally, just prior to implantation, and spatially, only at the site of blastocyst apposition (Das, S. K., Wang, X. N., Paria, B. C., Damm, D., Abraham, J. A., Klagsbrun, M., Andrews, G. K. and Dey, S. K. (1994) Development 120, 1071–1083). HB-EGF is synthesized as a transmembrane protein (HB-EGF TM) that can be processed to release the soluble growth factor. An antibody that cross-reacts only with the transmembrane form detected HB-EGF TM in uterine luminal epithelium in a spatial manner similar to that of HB-EGF mRNA. HB-EGF TM is a juxtacrine growth factor that mediates cell-cell contact. To ascertain if HB-EGF TM could be an adhesion factor for blastocysts, a mouse cell line synthesizing human HB-EGF TM was co-cultured with mouse blastocysts. Cells synthesizing HB-EGF TM adhered to day-4 mouse blastocysts more extensively than parental cells or cells synthesizing a constitutively secreted form of HB-EGF. Adhesion of cells synthesizing HB-EGF TM to blastocysts was inhibited by excess recombinant HB-EGF but less so by TGF-alpha. Adhesion was also inhibited by the synthetic peptide P21 corresponding to the HB-EGF heparin binding domain, and by incubating the blastocysts with heparinase. In addition, adhesion to delayed implanting dormant blastocysts, which lack EGF receptor (EGFR), was diminished relative to normal blastocysts. These results suggested that adhesion between blastocysts and cells synthesizing HB-EGF TM was mediated via interaction with both blastocyst EGFR and heparan sulfate proteoglycan (HSPG). It was concluded that HB-EGF TM, which is synthesized exclusively in the luminal epithelium at the site of blastocyst apposition, and which is a juxtacrine adhesion factor for blastocysts, could be one of the mediators of blastocyst adhesion to the uterus in the process of implantation.

Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation

Development ◽  
1994 ◽  
Vol 120 (5) ◽  
pp. 1071-1083 ◽  
Author(s):  
S.K. Das ◽  
X.N. Wang ◽  
B.C. Paria ◽  
D. Damm ◽  
J.A. Abraham ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Heparan Sulphate ◽  
Luminal Epithelium ◽  
Heparin Binding ◽  
Mouse Uterus ◽  
Growth Factor Gene ◽  
Heparan Sulphate Proteoglycans ◽  
Egf Family

Heparin-binding EGF-like growth factor (HB-EGF) is a newly discovered member of the EGF family of growth factors. HB-EGF can bind to two loci on cell surfaces, heparan sulphate proteoglycans and EGF-receptor (EGF-R), and either one or both of these interactions could play a role in cell-cell interactions. In the rodent, increased endometrial vascular permeability at the site of blastocyst apposition is considered to be an earliest discernible prerequisite event in the process of implantation and this event coincides with the initial attachment reaction between the blastocyst trophectoderm and uterine luminal epithelium. This investigation demonstrates that the HB-EGF gene is expressed in the mouse uterine luminal epithelium surrounding the blastocyst 6–7 hours before the attachment reaction that occurs at 2200–2300 hours on day 4 of pregnancy. It was further demonstrated that this gene is not expressed in the luminal epithelium at the site of the blastocyst apposition during the progesterone-maintained delayed implantation, but is readily induced in the luminal epithelium surrounding an activated blastocyst after termination of the delay by an estrogen injection. In vitro studies showed that HB-EGF induced blastocyst EGF-R autophosphorylation, and promoted blastocyst growth, zona-hatching and trophoblast outgrowth. These results suggest possible interactions between the uterine HB-EGF and blastocyst EGF-R very early in the process of implantation, earlier than any other embryo-uterine interactions defined to date at the molecular level.

Hepatoma-Derived Growth Factor (HDGF): A New Heparin-Binding Growth Factor Identified in Leiomyomas and Normal Myometrium

1998 ◽  
Vol 5 (1) ◽  
pp. 180A-180A
Author(s):  
M ISHIKAWA ◽  
S TAKASHIMA ◽  
H NAKAMURA ◽  
M KLAGSBRUN ◽  
R NOWAK
Keyword(s):  
Growth Factor ◽  
Heparin Binding

scholarly journals Molecular signaling at the fusion stage of the mouse mandibular arch: involvement of insulin-like growth factor family

2013 ◽  
Vol 57 (5) ◽  
pp. 399-406 ◽  
Author(s):  
Kazuya Fujita ◽  
Yuji Taya ◽  
Yoshihito Shimazu ◽  
Takaaki Aoba ◽  
Yuuichi Soeno
Keyword(s):  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Molecular Signaling ◽  
Mandibular Arch
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