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.
Reference
Bernfield
M.
, Kokenyesi
R.
, Kato
M.
, Hinkes
M. T.
, Spring
J.
, Gallo
R. L.
, Lose
E. J.
(1992
) Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans.
Annu. Rev. Cell Biol
8
, 365
–393
Bruce-Mann
G.
, Fowler
K. J.
, Gabriel
A.
, Nice
E. C.
, Linsay
W. R.
, Dunn
A. R.
(1993
) Mice with a null mutation of the TGF-gene have abnormal skin architecture, wavy hairs and curly whiskers and often develop corneal inflammation.
Cell
73
, 249
–261
Carraway
K. L.
, Weber
J. L.
, Unger
M. J.
, Ledesma
J.
, Yu
N.
, Gassmann
M.
, Lai
C.
(1997
) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases.
Nature
387
, 512
–516
Chang
H.
, Riese
D. J.
, Gilbert
W.
, Stern
D. F.
, McMahan
U. J.
(1997
) Ligands for ErbB-family receptors encoded by a neuregulin-like gene.
Nature
387
, 509
–512
Dardik
A.
, Smith
R. M.
, Schultz
R. M.
(1992
) Colocalization of transforming growth factor-(and a functional epidermal growth factor receptor (EGFR) to the inner cell mass and preferential localization of the EGFR on the basolateral surface of the trophectoderm in the mouse blastocyst.
Dev. Biol
154
, 393
–409
Das
S. K.
, Wang
X.-N.
, Paria
B. C.
, Damm
D.
, Abraham
J. A.
, Klagsbrun
M.
, Andrews
G. K.
, Dey
S. K.
(1994
) 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
120
, 1071
–1083
Das
S. K.
, Chakraborty
I.
, Paria
B. C.
, Wang
X.-N.
, Plowman
G.
, Dey
S. K.
(1995
) Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus.
Mol. Endocrinol
9
, 691
–705
Das
S. K.
, Das
N.
, Wang
J.
, Lim
H.
, Schryver
B.
, Plowman
G. D.
, Dey
S. K.
(1997
) Expression of betacellulin and epiregulin genes in the mouse uterus temporally by the blastocyst solely at the site of its apposition is coincident with the ‘window’ of implantation.
Dev. Biol
190
, 178
–190
Earp
H. S.
, Dawson
T. L.
, Li
X.
, Yu
H.
(1995
) Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research.
Breast Cancer Res. Treat
35
, 115
–132
Elenius
K.
, Corfas
G.
, Paul
S.
, Choi
C. J.
, Rio
C.
, Plowman
G. D.
, Klagsbrun
M.
(1997
) A novel juxtamembrane isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester.
J. Biol. Chem
272
, 26761
–26768
Elenius
K.
, Paul
S.
, Allison
G.
, Sun
J.
, Klagsbrun
M.
(1997
) Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation.
EMBO J
16
, 1268
–1278
Falls
D. L.
, Rosen
K. M.
, Corfas
G.
, Lane
W. S.
, Fischbach
G. D.
(1993
) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family.
Cell
72
, 801
–815
FitzGerald
D. J. P.
, Morris
R. E.
, Saelinger
C. B.
(1980
) Receptor-mediated internalization of Pseudomonas toxin by mouse fibroblasts.
Cell
21
, 867
–873
Gassmann
M.
, Casagranda
F.
, Orioli
D.
, Simon
H.
, Lai
C.
, Klein
R.
, Lemke
G.
(1995
) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor.
Nature
378
, 390
–394
Graus-Porta
D.
, Beerli
R. R.
, Daly
J. M.
, Hynes
N. E.
(1997
) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling.
EMBO J
16
, 1647
–1655
Higashiyama
S.
, Abraham
J. A.
, Miller
J.
, Fiddes
J. C.
, Klagsbrun
M.
(1991
) A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF.
Science
251
, 936
–939
Higashiyama
S.
, Abraham
J. A.
, Klagsbrun
M.
(1993
) Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate.
J. Cell Biol
122
, 933
–940
Higashiyama
S.
, Horikawa
M.
, Yamada
K.
, Ichino
N.
, Nakano
N.
, Nakagawa
T.
, Miyagawa
J.
, Matsushita
N.
, Nagatsu
T.
, Taniguchi
N.
, Ishiguro
H.
(1997
) A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4.
Biochem. J
122
, 675
–680
Holmes
W. E.
, Sliwkowski
M. X.
, Akita
R. W.
, Henzel
W. J.
, Lee
J.
, Park
J. W.
, Yansura
D.
, Abadi
N.
, Raab
H.
, Lewis
G. D.
, Shepard
H. M.
, Kuang
W.-J.
, Wood
W. I.
, Goeddel
D. V.
, Vandlen
R. L.
(1992
) Identification of heregulin, a specific activator of p185ErbB2.
Science
256
, 1205
–1210
Hynes
N. E.
, Stern
D. F.
(1994
) The biology of erbB-2/neu/HER-2 and its role in cancer.
Biochim. Biophys. Acta
1198
, 165
–184
Komurasaki
T.
, Toyoda
H.
, Uchida
D.
, Morimoto
S.
(1997
) Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4.
Oncogene
15
, 2841
–2848
Luetteke
N. C.
, Qui
T. H.
, Peiffer
R. L.
, Oliver
P.
, Smithies
O.
, Lee
D. C.
(1993
) TGF-deficiency results in hai follicle and eye abnormalities in targeted and waved-1 mice.
Cell
73
, 263
–278
Marchionni
M. A.
, Goodearl
A. D. J.
, Chen
M. S.
, Bermingham-McDonogh
O.
, Kirk
C.
, Hendricks
M.
, Danehy
F.
, Misumi
D.
, Sudhalter
J.
, Kobayashi
K.
, Wroblewski
D.
, Lynch
C.
, Baldassare
M.
, Hiles
I.
, Davis
J. B.
, Hsuan
J. J.
, Totty
N. F.
, Otsu
M.
, McBurney
R. N.
, Waterfield
M. D.
, Stroobant
P.
, Gwynne
D.
(1993
) Glial growth factors are alternatively spliced ErbB2 ligands expresses in the nervous system.
Nature
362
, 312
–318
Martin
K. L.
, Barlow
D. H.
, Sargent
I. L.
(1998
) Heparin-binding epidermal growth factor significantly improves human blastocyst development and hatching in serum-free medium.
Hum. Reprod
13
, 1645
–1652
Menezo
Y.
, Hazout
A.
, Dumont
M.
, Herbaut
N.
, Nicollet
B.
(1992
) Coculture of embryos on Vero cells and transfer of blastocysts in humans.
Hum. Reprod
7
, 101
–106
Mesri
E. A.
, Ono
M.
, Kreitman
R. J.
, Klagsbrun
M.
, Pastan
I.
(1994
) The heparin-binding domain of heparin-binding EGF-like growth factor can target Pseudomonas exotoxin to kill cells exclusively through heparan sulfate proteoglycans.
J. Cell Sci
107
, 2599
–2608
Miettinen
P. J.
, Berger
J. E.
, Meneses
J.
, Phung
Y.
, Pedersen
R. A.
, Werb
Z.
, Derynck
R.
(1995
) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor.
Nature
376
, 337
–341
Paria
B. C.
, Das
S. K.
, Andrews
G. K.
, Dey
S. K.
(1993
) Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation.
Proc. Natl. Acad. Sci. USA
90
, 55
–59
Paria
B. C.
, Huet-Hudson
Y. M.
, Dey
S. K.
(1993
) Blastocyst's state of activity determines the ‘window’ of implantation in the receptive mouse uterus.
Proc. Natl. Acad. Sci. USA
90
, 10159
–10162
Parr
E. L.
, Tung
H. N.
, Parr
M. B.
(1987
) Apoptosis as the mode of uterine epithelial cell death during embryo implantation in mice and rats.
Biol. Reprod
36
, 211
–225
Raab
G.
, Kover
K.
, Paria
B. C.
, Dey
S. K.
, Ezzell
R. M.
, Klagsbrun
M.
(1996
) Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor.
Development
122
, 637
–645
Riese
D. J.
, Bermingham
Y.
, van Raaij
T. M.
, Buckley
S.
, Plowman
G. D.
, Stern
D. F.
(1996
) Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta.
Oncogene
12
, 345
–353
Riese
D. J.
, Kim
E.
, Buckley
S.
, Elenius
K.
, Klagsbrun
M.
, Plowman
G. D.
, Stern
D. F.
(1996
) The epidermal growth factor receptor couples transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, and amphiregulin to Neu, ErbB-3, and ErbB-4.
J. Biol. Chem
271
, 20047
–20052
Shing
Y.
, Christofori
G.
, Hanahan
D.
, Ono
Y.
, Sasada
R.
, Igarashi
K.
, Folkman
J.
(1993
) Betacellulin: a mitogen from pancreatic beta cell tumors.
Science
259
, 1604
–1607
Shoyab
M.
, Plowman
G. D.
, McDonald
V. L.
, Bradley
J. G.
, Todaro
G. J.
(1989
) Structure and function of human amphiregulin: a member of the epidermal growth factor family.
Science
243
, 1074
–1076
Sibilia
M.
, Wagner
E. F.
(1995
) Strain-dependent epithelial defects in mice lacking the EGF receptor.
Science
269
, 234
–238
Sibilia
M.
, Steinbach
J. P.
, Stingl
L.
, Aguzzi
A.
, Wagner
E. F.
(1998
) A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor.
EMBO J
17
, 719
–731
Smith
S. E.
, French
M. M.
, Julian
J.
, Paria
B. C.
, Dey
S. K.
, Carson
D. D.
(1997
) Expression of heparan sulfate proteoglycan (perlecan) in the mouse blastocyst is regulated during normal and delayed implantation.
Dev. Biol
184
, 38
–47
Surveyor
G. A.
, Gendler
S. J.
, Pemberton
L.
, Das
S. K.
, Chakraborty
I.
, Julian
J.
, Pimental
R. A.
, Wegner
C. C.
, Dey
S. K.
, Carson
D. D.
(1995
) Expression and steroid hormonal control of Muc-1 in the mouse uterus.
Endocrinol
136
, 3639
–3647
Tamada
H.
, Das
S. K.
, Andrews
G. K.
, Dey
S. K.
(1991
) Cell type-specific expression of transforming growth factor-(in the mouse uterus during the peri-implantation period.
Biol. Reprod
45
, 365
–372
Thompson
S. A.
, Higashiyama
S.
, Wood
K.
, Pollitt
N. S.
, Damm
D.
, McEnroe
G.
, Garrick
B.
, Ashton
N.
, Lau
K.
, Hancock
N.
, Klagsbrun
M.
, Abraham
J. A.
(1994
) Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin.
J. Biol. Chem
269
, 2541
–2549
Threadgill
D. W.
, Dlugosz
A. A.
, Hansen
L. A.
, Tennenbaum
T.
, Lichti
U.
, Yee
D.
, LaMantia
C.
, Mourton
T.
, Herrup
K.
, Harris
R. C.
, Barnard
J. A.
, Yuspa
S. H.
, Coffey
R. J.
, Magnuson
T.
(1995
) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.
Science
269
, 230
–234
Toyoda
H.
, Komurasaki
T.
, Uchida
D.
, Takayama
Y.
, Isobe
T.
, Okuyama
T.
, Hanada
K.
(1995
) Epiregulin. A novel epidermal growth factor with mitogenic activity for rat primary hepatocytes.
J. Biol. Chem
270
, 7495
–7500
Ullrich
A.
, Coussens
L.
, Hayflick
J. S.
, Dull
T. J.
, Gray
A.
, Tam
A. W.
, Lee
J.
, Yarden
Y.
, Libermann
T. A.
, Schlessinger
J.
, Downward
J.
, Mayes
E. L. V.
, Whittle
N.
, Waterfield
M. D.
, Seeburg
P. H.
(1984
) Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.
Nature
309
, 418
–425
Wang
L. M.
, Kuo
A.
, Alimandi
M.
, Veri
M. C.
, Lee
C. C.
, Kapoor
V.
, Ellmore
N.
, Chen
X. H.
, Pierce
J. H.
(1998
) ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4.
Proc. Natl. Acad. Sci. USA
95
, 6809
–6814
Wen
D.
, Peles
E.
, Cupples
R.
, Suggs
S. V.
, Bacus
S. S.
, Luo
Y.
, Trail
G.
, Hu
S.
, Silbiger
S. M.
, Levy
R. V.
, Koski
R. A.
, Lu
H. S.
, Yarden
Y.
(1992
) Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit.
Cell
69
, 559
–572
Yanagishita
M.
, Hascall
V. C.
(1992
) Cell surface heparan sulfate proteoglycans.
J. Biol. Chem
267
, 9451
–9454
Yoo
H. J.
, Barlow
D. H.
, Mardon
H. J.
(1997
) Temporal and spatial regulation of expression of heparin-binding epidermal growth factor-like growth factor in the human endometrium: a possible role in blastocyst implantation.
Dev. Genet
21
, 102
–108
Yoshinaga
K.
, Adams
C. E.
(1966
) Delayed implantation in the spayed, progesterone-treated adult mouse.
J. Reprod. Fertil
12
, 593
–595
Zhang
D.
, Sliwkowski
M. X.
, Mark
M.
, Frantz
G.
, Akita
R.
, Sun
Y.
, Hillan
K.
, Crowley
C.
, Brush
J.
, Godowski
P. J.
(1997
) Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4.
Proc. Natl. Acad. Sci. USA
94
, 9562
–9567
This content is only available via PDF.
© 1999 by Company of Biologists
1999
-HUBSwebinar.jpg?versionId=4486)
(update)-InPreprints.png?versionId=4486)
