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www.rbmonline.com/Article/2454 on web 5 October 2006

Outlook
Embryo implantation: the molecular mechanism
remains elusive
John Aplin received his initial training in chemistry at Queen’s College Oxford, and in
biophysics at the University of British Columbia where he first became interested in
glycobiology and the cell surface. As a ‘post-doc’ at the MRC laboratories in Mill Hill,
London his interests turned to the biology of cell adhesion. Chance events led him into
reproductive biology, most notably implantation and placental development. He is currently
Professor of Reproductive Biomedicine at the University of Manchester where he is a
member of the Maternal and Fetal Health Research Centre in the Medical School, with a
cross-appointment in the Faculty of Life Sciences.

Dr John Aplin
JD Aplin
Division of Human Development, Medical School, University of Manchester, UK
Correspondence: Research Floor, St Mary’s Hospital, Manchester M13 0JH, UK; e-mail: john.aplin@manchester.
ac.uk

Abstract
Low rates of implantation are an impediment to more efficient assisted reproduction techniques. Improved endometrial
receptivity and embryo preparation should lead to higher pregnancy rates, lower rates of early pregnancy failure and fewer
multiple pregnancies. As the first site of contact between embryo and endometrium, the luminal epithelium (LE) is responsible
for the non-receptive status of proliferative and early secretory tissue, and transformation to receptivity in the mid-secretory
phase presumably requires alterations in expression, organization or activation of adhesion systems. Luminal cells are less
abundant than their glandular counterparts, and are under-represented in global tissue datasets. Furthermore, alterations in
cell surface composition can be readily accomplished by mechanisms that do not rely on altered transcription or translation.
Current data from in-vitro models are consistent with initial attachment to mucin in the apical glycocalyx, perhaps via a
carbohydrate-mediated interaction, after which the epithelial phenotype is modified by a medium- or short-range embryonic
signal. A cascade of interactions follows, mediating embryo migration across the epithelium. Strikingly, numerous potential
mediators of adhesion at implantation are located in the lateral rather than the apical surface of LE cells. Attached embryos
appear to gain rapid access to this highly adhesive lateral membrane domain.

Keywords: adhesion molecule, endometrium, epithelial polarity, glycocalyx, implantation, mucin

are cuboidal rather than columnar; they show less pronounced

The implantation window is
regulated by endometrial luminal
epithelium
Observations made following embryo replacement indicate that
the human endometrium is receptive to an implanting embryo
from about 6–10 days after the LH peak (Bergh and Navot,
1992; Aplin, 2000). Hatched blastocysts attach non-selectively to
endometrial stromal cells in vitro (Carver et al., 2003) as well as
to tissue culture dishes, indicating that it is the luminal epithelium
that confers upon the uterus its unique property of resistance to
implantation in phases other than the mid-secretory. Though both
originate from progenitor cells in the basal glands during post-
menstrual regeneration, luminal epithelial (LE) cells are distinct
from their glandular (GE) counterparts (Dockery, 2002): they
secretory and organellar changes in the secretory phase; they
develop mid-secretory uterodomes or pinopodes, apical cell
surface swellings that have been suggested as an attribute of
receptive tissue (Murphy, 2000; Lopata et al., 2002); and there
are numerous molecular markers that indicate compositional
distinctions between the two (Seif and Aplin, 1990; Aplin et al.,
1998; ). In the mouse, comparative microarray analysis of the GE
and LE transcriptomes at the time of implantation (Niklaus and
Pollard, 2006) indicates that though most products are common,
about 280 genes significantly differ in expression. These fall into
numerous functional categories, but one important observation
is the presence of immune defence gene products in the LE, a
reminder that it has a primary barrier function in repelling micro-
organisms in the upper reproductive tract. Discussion of the
effect of ovarian stimulation regimes and hormone replacement
therapy on receptivity has been clouded by the lack of a precise 833
 Outlook - Molecular mechanism of embryo implantation - JD Aplin
understanding of the key attributes (molecular or structural) that
confer receptive status on endometrium. In fact, there is evidence
that a range of phenotypes will support implantation; it may well
be that healthy embryos can to some extent overcome endometrial
defects.
Identifying the molecular mediators
of implantation
Common assumptions that underpin experimental approaches
to the identification of components involved in embryo
attachment and subsequent phases of implantation deserve closer
scrutiny: (i) it appears imperative that protein expression should
occur in the implantation phase LE and in the trophectoderm of the
hatched blastocyst; (ii) since initial attachment occurs at the apical
side of maternal cells, display at this surface appears important;
(iii) candidate components on the maternal and embryonic surfaces
should be capable of receptor−ligand interaction; (iv) in order to
explain varying receptivity, it is often assumed that expression
will be regulated with highest levels in the mid-secretory phase;
and (v) if mice null for the respective gene product show impaired
implantation, the hypothesis that there is involvement in humans
is strengthened, though by no means proven.
Microarray studies based on assumption (iv) have sought
to identify a molecular signature characteristic of receptive
endometrium (see, e.g. Ponnampalam et al., 2004; Talbi et al.,
2006). Though informative in other respects, these studies have
not thus far been particularly helpful in identifying candidate gene
products or pathways that might play a role in embryo attachment.
One problem is that LE contributes a minority of the cells present
in a typical endometrial biopsy; another is that endometrial tissue
composition has inherent variability, as seen very obviously in
glandular and stromal histology (Buckley and Fox, 1989). This
leads to uncertainty in histological dating (Coutifaris et al., 2004;
Myers et al., 2004). Furthermore, the proportion of epithelial and
stromal cell-derived mRNA in similarly timed biopsies can vary
widely (Jasper et al., 2006).
Epithelial polarity and implantation
Work carried out in earlier decades led to recognition that epithelial
polarity plays a key role in uterine function (Denker, 1993;
Glasser and Mulholland, 1993). Thus, for example, key aspects of
the steroid response in endometrial epithelial cells are controlled
indirectly by paracrine signals reaching the basal epithelial surface
from receptor-positive, steroid-responsive stromal cells (Cooke et
al., 2002). The apical epithelial surface, as well as providing an
immune barrier (innate and acquired via immunoglobulin A), is
clearly the first site of interaction with the embryo. To prevent
epithelial cavities from sealing up, apical surfaces must normally
be non-self-adhesive. Thus, the hypothesis arose that implantation
might occur in the context of altered maternal epithelial polarity.
The epithelial glycocalyx, which contains MUC1 (Aplin et
al.,, 1998; Meseguer et al., 2001) and other higher molecular
mass mucin glycoproteins MUC4 (Idris and Carraway, 2000),
MUC6 (Gipson et al., 1997) and MUC16 (CA125; Mylonas et
al., 2003), is a key attribute of the apical epithelial surface. Its
absence from basolateral cell surfaces in normal luminal (and
834 glandular) endometrial epithelium defines these cells as showing
a primary polarity and an apical barrier. In carcinoma cells, this
tightly defined polarity of MUC1 expression is lost and novel
glycoforms appear. There is evidence that the glycocalyx is
altered at the surface of uterodomes in the mid-secretory LE, with
loss of MUC1 epitopes (Horne et al., 2005).
First phase attachment
MUC1 can play a dual role in relation to cellular interactions.
By virtue of high expression at the cell surface, density of
glycosylation and extended conformation, it is capable of
sterically hindering interaction with other cell surfaces mediated
by families of conformationally smaller adhesion molecules such
as integrins and cadherins (Hilkens et al., 1992). On the other hand,
some isoforms of MUC-1 are able to bind intracellular adhesion
molecule (ICAM)-1 (via the exposed core protein) (Regimbald
et al., 1996), and MUC-1 glycoforms carrying selectin ligands
can be observed in the endometrium (Hey and Aplin, 1996). This
has led to the suggestion that L-selectin on the trophectodermal
surface of the blastocyst might mediate initial interaction with
ligand on the LE (Genbacev et al., 2003), but other studies have
failed to detect L-selectin on the blastocyst (Campbell et al.,
1995b; Bloor et al., 2002) and more work is required to clarify
this important point. MUC-1 is polymorphic, with expression at
the cell surface of two alleles differing in the number of tandem
repeats in the mucin domain. The suggestion has been made that
variation at this locus may be associated with infertility, but this
requires further investigation (Goulart et al., 2004).
Clearance of apical surface mucin by
attaching embryos
In mouse and rat, MUC1 is strongly expressed at the apical LE
surface, but it is removed under maternal hormonal control in
advance of embryo attachment (reviewed in Aplin and Kimber,
2004). This occurs even in leukaemia inhibitory factor (LIF)-null
female mice, which have a block to implantation (Chen et al.,
2000). Here, embryos appear to attach normally to the epithelial
surface, but implantation arrests thereafter (Fouladi-Nashta et al.,
2005). MUC1 is also lost from luminal epithelium in macaques
under maternal control (Julian et al., 2005). In humans, MUC-1
is continuously present at the luminal surface of the endometrial
cavity throughout the cycle, with an increase in the secretory
phase (Hey et al., 1994). However, the human embryo attaches
to primary cultured MUC1+ endometrial epithelial monolayers,
and MUC1 immunostaining is lost from cells beneath and
immediately adjacent to the attachment site (Meseguer et al.,
2001). Surprisingly, mouse embryos also appear to be capable
of removing MUC1 from the surface of epithelial cells beneath
and adjacent to their site of attachment, suggesting that a rescue
pathway may be available in this species for circumstances in
which MUC1 is not fully cleared under maternal control. The
mechanism of clearance is still unknown, though it has been
shown that both ADAM 17 (TACE) and matrix metalloproteinase
(MMP)-14 (MT-MMP1) are capable of releasing MUC1 from the
cell surface (Thathiah et al., 2003; Thathiah and Carson, 2004).
It is clear that soluble signals pass locally between the embryo
and receptors on maternal cells: chemokines (Dominguez et al.,
2003), leptin (Cervero et al., 2005) and chorionic gonadotrophin
(Zhou et al., 1999; Cameo et al., 2004) may all play a role in
mediating this early dialogue.
 Outlook - Molecular mechanism of embryo implantation - JD Aplin

Based on these findings, one can postulate that initial attachment as an adhesion substrate and a barrier. Uterodomes represent a
to glycocalyx is followed by lateral clearance of mucin, leading specialized area of LE plasma membrane that could be used for
to interaction of trophoblast with higher affinity epithelial attachment, but this has not been observed (Bentin-Ley, 2000).
adhesion systems (Figure 1). Thus, the glycocalyx could act both

Figure 1. (a) Initial attachment is to the glycocalyx and may be mediated by a lectin−carbohydrate interaction. The lateral luminal
epithelium (LE) membranes are rich in adhesion molecules. (b) Second phase attachment follows the clearance of apical glycocalyx
in response to an embryonic signal. The lateral LE borders open and trophectodermal processes insert between the LE cells. MUC
1 = mucin 1; OPN = osteopontin.
835
 Outlook - Molecular mechanism of embryo implantation - JD Aplin
This initial interaction locates the embryo within a specific
area of the uterine surface. Short range signalling to maternal
epithelial cells can then occur, leading to glycocalyx clearance.
This is a test of viability for the embryo, and poor quality (e.g.
monosomic) blastocysts may fail at this stage. At the same time,
it places the state of receptivity in a new light: the ability of
the epithelium to respond to embryo-derived signals (Quenby
et al., 2002).
Second phase attachment:
candidate adhesion systems
First phase attachment is presumed to be followed closely
by adhesion of trophectoderm to non-mucin receptors at
the epithelial surface. There are numerous hurdles to the
identification of molecular mediators, of which the most serious
is that it is not possible to obtain sufficient human embryos to
carry out well-controlled studies of molecular pathways. Mouse
embryos may provide useful clues, and studies of fertility in
mouse gene knockouts are in some cases instructive.
Candidate adhesion systems have been reviewed in detail
elsewhere (Aplin, 1997; Kimber and Spanswick, 2000; Aplin
and Kimber, 2004). A few are mentioned here in brief. In
assessing possible mediators, the Human Protein Atlas, part of
the Human Proteome Organisation (HUPO) human antibody
initiative (http://www.proteinatlas.org), is a very useful resource
that aims eventually to show the distribution of all proteins in a
wide range of human tissues. Several of the proteins discussed
below are included in current releases of the atlas with high
quality immunolocalization in endometrium.
Basigin, also known as CD147 and EMMPRIN, is a membrane-
spanning immunoglobulin superfamily member with multiple
binding partners at the cell surface. It may be activated by
direct homotypic interaction between adjacent cells, but is
best known as an activator of MMP activity. In both mice and
rats it is expressed in LE on day 1 of pregnancy under the
influence of oestrogen, is down-regulated but then reappears
locally in response to an embryonic stimulus on day 4 (Xiao
et al., 2002a,b). Implantation rates are severely compromised
in animals lacking basigin (Igakura et al., 1998; Kuno et al.,
1998). Basigin is expressed most prominently at the lateral
epithelial surface of endometrial epithelial cells in human and
rodent. It is also expressed on pre-implantation embryos.
CD44 is another single pass transmembrane glycoprotein. It
shows a complex pattern of alternative splicing with several
forms observed in endometrium (Behzad et al., 1994). It
is expressed in pre-implantation embryos (Campbell et al.,
1995a). It is associated with cell migration and has numerous
binding partners including hyaluronate and osteopontin. Null
mice are fertile. In endometrium, CD44 shows a predominantly
lateral distribution in both GE and LE (Behzad et al., 1994).
Osteopontin (OPN; also known as SPP1) is a secreted
glycoprotein that is regulated by progesterone (Apparao et al.,
2001) and reaches a maximum in the secretory phase of the cycle
when it immunolocalizes predominantly to the apical cytoplasm
of LE and GE cells. It has multiple binding partners including
integrins α4β1, αvβ3, αvβ5, αvβ6 and specific splice variants of
836 CD44 (v3, v6). Null mice are fertile. In ruminants exhibiting
epitheliochorial implantation, OPN localizes precisely to the
interface between trophectoderm and LE (Johnson et al., 2003).
The possibility that OPN could bridge between cell surface
ligands such as integrins and CD44 on the trophectoderm and
LE has not been tested directly.
Integrins of the β1 and αv subfamilies have been widely
discussed as potential mediators of implantation (see Aplin
and Kimber, 2004). Mice lacking the integrin β1 subunit fail
to implant, but this intervention deletes at least 10 different
integrins. In contrast, mice null for αv are fertile. Integrin αvβ3
exhibits a mid-secretory phase increase in expression by virtue
of an increase in β3 abundance (Lessey, 2002). Experimental
evidence has been reported (blocking antibody action in vivo)
that suggests a role for integrin α4β1 in mouse implantation
(Basak et al., 2002). Integrin expression on epithelial cells is
highly variable between different areas of both GE and LE.
In general, expression is substantially higher in the former.
Integrins of both types are again more abundant on lateral (and
basal) epithelial surfaces than at the apical surface, though
some apical expression is detectable. Integrins are also widely
expressed on stromal cells.
Trophinin is a membrane component discovered in a screen
for components mediating the attachment of teratocarcinoma
cells to a uterine epithelial cell line (Fukuda et al., 1995).
There is evidence that human chorionic gonadotrophin can
induce local expression of trophinin by maternal epithelial cells
(Nakayama et al., 2003). Functional trophinin associates with
two cytoplasmic proteins, tastin and bystin, and the complex
appears to be apically displayed (Fukuda and Nozawa, 1999). It
is not absolutely required for early implantation in mice (Nadano
et al., 2002), but remains a possible candidate in primates.
CD9 is a member of the tetraspanin family of accessory
proteins. It can act as a receptor for the family of pregnancy-
specific glycoproteins (PSG) produced by trophoblast
(Wynne et al., 2006), as well as associating laterally with
β1 integrins in the plasma membrane (Park et al., 2000). Its
distribution in endometrium is again largely in the lateral
membranes of epithelial cells, including the LE. It is also
expressed in blastocysts. Blocking antibodies to CD9 added
in vitro to mouse embryos attaching to epithelial monolayers
stimulated trophoblast outgrowth, though there was no effect
on attachment rate. MMP-2 production was stimulated via the
phosphatidylinositol 3-kinase pathway. Intrauterine injection of
the antibodies on day 4 of mouse pregnancy increased the number
of implantation sites (Liu et al., 2006). These experiments
suggest CD9 as an inhibitor or regulator of implantation, and in
agreement with this hypothesis, CD9-replete embryos implant
normally in CD9-null mothers (Wynne et al., 2006).
Regulation of adhesion systems
that mediate implantation
It is striking that several molecular systems that might potentially
play a role in the epithelial phases of embryo implantation are
predominantly localized to the lateral cell membranes of LE
cells when studies are carried out in non-conception cycles.
Furthermore, few show substantial evidence of hormonal
regulation, either when studied directly at protein level or when
large scale transcriptomic screens have been carried out. There

Table 1. Non-transcriptional, non-translational mechanisms for altering
receptivity at the endometrial luminal epithelium.
Gross membrane morphology, e.g. uterodomes
Proteolysis and shedding
Redistribution of surface components between membrane domains
Association with accessory molecules
Trafficking from endosomal compartments to and from the cell surface
Activation, e.g. via phosphorylation
Other enzymatic modifications, e.g. cross-linking, glycosylation
Cytoskeletal association
Lipid association
is compelling evidence that local signalling occurs between the
embryo and LE at implantation and it is entirely plausible that
such signalling triggers a reorganization of the LE surface with
alteration of polarity and redistribution of components between
membrane domains. Table 1 lists several mechanisms by which
alteration in plasma membrane composition or activity could
occur independent of transcription or translation.
The lateral borders of LE cells undergo striking changes at the
time of implantation in several species. For example, desmosomes
are reduced in the mouse uterine luminal epithelium during the
preimplantation period of pregnancy (Illingworth et al., 2000),
and gap junctional connections between LE cells are exquisitely
modulated by embryonic signals in the implantation chamber
(Grummer et al., 2004). Tight junctions move to a deeper level
in LE in mid-secretory phase human endometrium (Murphy et
al., 1982), and the tight junction proteins claudins 1, 4 and 5
are concentrated in the lower parts of lateral LE cell borders
(http://www.proteinatlas.org). It is noteworthy that when human
embryos attach to primary human epithelial cells, transmission
electron microscopic examination reveals direct membrane-
to-membrane interactions between the trophectoderm and the
lateral (not apical) surfaces of endometrial cells (Bentin-Ley,
2000). This appears to occur after disruption of apical junctional
complexes, with opening up of spaces between the lateral
borders of epithelial cells, and intrusion of trophectodermal
processes. There is sharing of apical junctional complexes and
desmosomes between trophectoderm and LE cells (Lopata et
al., 2002; Figure 1).
Thus, the interaction between the embryo and the apical LE
surface is transient. Interactions occurring at the highly hydrated
glycocalyx are difficult to visualize in electron microscopy
because of dehydration artefacts arising at processing. The store
of cell adhesion molecules in lateral LE membranes may be
called into action early in the epithelial phase of implantation,
either following attachment to the glycocalyx or immediately
after its clearance.
Returning to the criteria listed at the start of this article,
transcriptional regulation of components mediating attachment
during the menstrual cycle is a questionable assumption.
Given local signalling at the implantation site, and the many
mechanisms available to cells for rapid alteration of cell surface
composition, neither is it essential that the key adhesion ligand–
Outlook - Molecular mechanism of embryo implantation - JD Aplin
receptor systems be displayed at the apical LE surface in the
mid-secretory phase of non-conception cycles. Mouse mutants
with impaired implantation are useful in hypothesis generation,
but the extent to which embryo attachment in human uses the
same ligand–receptor systems remains to be demonstrated.
References
Aplin JD 2000 The cell biological basis of human implantation.
Baillière’s Best Practice and Research. Clinical Obstetrics and
Gynaecology 14, 757–764.
Aplin JD 1997 Adhesion molecules in implantation. Reviews of
Reproduction 2, 84–93.
Aplin JD, Kimber SJ 2004 Trophoblast-uterine interactions at
implantation. Reproductive Biology and Endocrinology 2, 48.
Aplin JD, Hey NA, Graham RA 1998 Human endometrial MUC1
carries keratan sulfate: characteristic glycoforms in the luminal
epithelium at receptivity. Glycobiology 8, 269–276.
Apparao KB, Murray MJ, Fritz MA et al. 2001 Osteopontin and its
receptor αvβ3 integrin are coexpressed in the human endometrium
during the menstrual cycle but regulated differentially. Journal of
Clinical Endocrinology and Metabolism 86, 4991–5000.
Basak S, Dhar R, Das C 2002 Steroids modulate the expression
of alpha4 integrin in mouse blastocysts and uterus during
implantation. Biology of Reproduction 66, 1784–1789.
Behzad F, Seif MW, Campbell S, Aplin JD 1994 Expression of
two isoforms of CD44 in human endometrium. Biology of
Reproduction 51, 739–747.
Bentin-Ley U 2000 Relevance of endometrial pinopodes for human
blastocyst implantation. Human Reproduction Supplement 6,
67–73.
Bergh PA, Navot D 1992 The impact of embryonic development and
endometrial maturity on the timing of implantation. Fertility and
Sterility 583, 537–542.
Bloor DJ, Metcalfe AD, Rutherford A et al. 2002 Expression of
cell adhesion molecules during human preimplantation embryo
development. Molecular Human Reproduction 8, 237–245.
Buckley CH, Fox H 1989 Biopsy Pathology of the Endometrium.
Chapman and Hall, London.
Cameo P, Srisuparp S, Strakova Z, Fazleabas AT 2004 Chorionic
gonadotropin and uterine dialogue in the primate. Reproductive
Biology and Endocrinology 2, 50.
Campbell S, Swann HR, Aplin JD et al. 1995a CD44 is expressed
throughout pre-implantation human embryo development. Human
Reproduction 10, 425–430.
Campbell S, Swann HR, Seif MW et al. 1995b Cell adhesion
molecules on the oocyte and preimplantation human embryo.
Human Reproduction 10, 1571–1578.
Carver J, Martin K, Spyropoulou I et al. 2003 An in-vitro model for
stromal invasion during implantation of the human blastocyst. 837
 Outlook - Molecular mechanism of embryo implantation - JD Aplin
Human Reproduction 18, 283–290.
Cervero A, Horcajadas JA, Dominguez F et al. 2005 Leptin system
in embryo development and implantation: a protein in search of a
function. Reproductive BioMedicine Online 10, 217–223.
Chen JR, Cheng JG, Shatzer T et al. 2000 Leukemia inhibitory factor
can substitute for nidatory estrogen and is essential to inducing a
receptive uterus for implantation but is not essential for subsequent
embryogenesis. Endocrinology 141, 4365–4372.
Cooke PS, Buchanan DL, Kurita T et al. 2002 In: Glasser SR, Aplin
JD, Giudice LN Tabibzadeh S (eds) The Endometrium. Taylor and
Francis, London, pp. 151–166.
Coutifaris C, Myers ER, Guzick DS et al. 2004 NICHD National Co-
operative Reproductive Medicine Network. Histological dating
of timed endometrial biopsy tissue is not related to fertility status.
Fertility and Sterility 82, 1264–1272.
Denker HW 1993 Implantation: a cell biological paradox. Journal of
Experimental Zoology 266, 541–558.
Dockery P 2002 The fine structure of the mature human endometrium.
In: Glasser SR, Aplin JD, Giudice LN, Tabibzadeh S (eds) The
Endometrium. Taylor and Francis, London, pp. 21–38.
Dominguez F, Galan A, Martin JJ et al. 2003 Hormonal and
embryonic regulation of chemokine receptors CXCR1, CXCR4,
CCR5 and CCR2B in the human endometrium and the human
blastocyst. Molecular Human Reproduction 9, 189–198.
Fouladi-Nashta AA, Jones CJ, Nijjar N et al. 2005 Characterization of
the uterine phenotype during the peri-implantation period for LIF-
null, MF1 strain mice. Developmental Biology 281, 1–21.
Fukuda MN, Nozawa S 1999 Trophinin, tastin, and bystin: a
complex mediating unique attachment between trophoblastic
and endometrial epithelial cells at their respective apical cell
membranes. Seminars in Reproductive Endocrinology 17, 229–234
Fukuda MN, Sato T, Nakayama J et al. 1995 Trophinin and tastin, a
novel cell adhesion molecule complex with potential involvement
in embryo implantation. Genes Development 9, 1199–1210.
Genbacev OD, Prakobphol A, Foulk RA et al. 2003 Trophoblast L-
selectin-mediated adhesion at the maternal−fetal interface. Science
299, 405–408.
Gipson IK, Ho SB, Spurr-Michaud SJ et al. 1997 Mucin genes
expressed by human female reproductive tract epithelia. Biology of
Reproduction 56, 999–1011.
Glasser SR, Mulholland J 1993 Receptivity is a polarity dependent
special function of hormonally regulated uterine epithelial cells.
Microscopy Research and Technique 25, 106–120.
Goulart LR, Vieira GS, Martelli L et al. 2004 Is MUC 1 polymorphism
associated with female infertility? Reproductive BioMedicine
Online 8, 477–482.
Grummer R, Hewitt SW, Traub O et al. 2004 Different regulatory
pathways of endometrial connexin expression: preimplantation
hormonal-mediated pathway versus embryo implantation-initiated
pathway. Biology of Reproduction 71, 273–281.
Hey NA, Aplin JD 1996 Sialyl-Lewis X and sialyl-Lewis A are
associated with MUC1 in human endometrium. Glycoconjugate
Journal 13, 769–779.
Hey NA, Graham RA, Seif MW, Aplin JD 1994 The polymorphic
epithelial mucin MUC1 in human endometrium is regulated with
maximal expression in the implantation phase. Journal of Clinical
Endocrinology and Metabolism 78, 337–342.
Hilkens J, Ligtenberg MJ, Vos HL, Litvinov SV 1992 Cell membrane-
associated mucins and their adhesion-modulating property. Trends
in Biochemical Sciences 17, 359–363.
Horne AW, Lalani EN, Margara RA et al. 2005 The expression
pattern of MUC1 glycoforms and other biomarkers of endometrial
receptivity in fertile and infertile women. Molecular Reproduction
and Development 72, 216–229.
Idris N, Carraway KL 2000 Regulation of sialomucin complex/Muc4
expression in rat uterine luminal epithelial cells by transforming
growth factor-beta: implications for blastocyst implantation.
Journal of Cellular Physiology 185, 310–316.
Igakura T, Kadomatsu K, Kaname T et al. 1998 A null mutation
in basigin, an immunoglobulin superfamily member, indicates
838 its important roles in peri-implantation development and
spermatogenesis. Developmental Biology 194, 152–165.
Jasper MJ, Tremellen KP, Robertson SA 2006 Reduced expression of
IL-6 and IL-1α mRNA in secretory phase endometrium of women
with recurrent miscarriage. Journal of Reproductive Biology, in
press.
Johnson GA, Burghardt RC, Bazer FW, Spencer TE 2003
Osteopontin: roles in implantation and placentation. Biology of
Reproduction 69, 1458–1471.
Julian J, Enders AC, Fazleabas AT, Carson DD 2005 Compartmental
distinctions in uterine Muc-1 expression during early pregnancy
in cynomolgous macaque and baboon. Human Reproduction 20,
1493–1503.
Kimber SJ, Spanswick C 2000 Blastocyst implantation: the adhesion
cascade. Seminars in Cell and Developmental Biology 11, 77–92.
Kuno N, Kadomatsu K, Fan QW et al. 1998 Female sterility in
mice lacking the basigin gene, which encodes a transmembrane
glycoprotein belonging to the immunoglobulin superfamily. FEBS
Letters 425 191–194.
Lessey BA 2002 Uterine factors in implantation. In: Glasser SR, Aplin
JD, Giudice L, Tabibzadeh S (eds) The Endometrium. Taylor and
Francis, London, pp. 208–228.
Liu WM, Cao YJ, Yang YJ et al. 2006 Tetraspanin CD9 regulates
invasion during mouse embryo implantation. Journal of Molecular
Endocrinology 36, 121–130.
Lopata A, Bentin-Ley U, Enders A 2002 ‘Pinopodes’ and implantation.
Reviews in Endocrine and Metabolic Disorders 3, 77–86.
Meseguer M, Aplin JD, Caballero-Campo P et al. 2001 Human
endometrial mucin MUC1 is up-regulated by progesterone and
down-regulated in vitro by the human blastocyst. Biology of
Reproduction 64, 590–601.
Murphy CR 2000 Understanding the apical surface markers of uterine
receptivity: pinopods–or uterodomes? Human Reproduction 15,
2451–2454.
Murphy CR, Swift JG, Need JA et al. 1982 A freeze-fracture electron
microscopic study of tight junctions of epithelial cells in the
human uterus. Anatomy and Embryology 163, 367–370.
Myers ER, Silva S, Barnhart K et al. 2004 NICHD National Co-
operative Reproductive Medicine Network. Interobserver
and intraobserver variability in the histological dating of the
endometrium in fertile and infertile women. Fertility and Sterility
82, 1278–1282.
Mylonas I, Makovitzky J, Richter DU et al. 2003
Immunohistochemical expression of the tumour marker CA-125 in
normal, hyperplastic and malignant endometrial tissue. Anticancer
Research 23, 1075–1080.
Nadano D, Sugihara K, Paria BC et al. 2002 Significant differences
between mouse and human trophinins are revealed by their
expression patterns and targeted disruption of mouse trophinin
gene. Biology of Reproduction 66, 313–321.
Nakayama J, Aoki D, Suga T et al. 2003 Implantation-dependent
expression of trophinin by maternal fallopian tube epithelia during
tubal pregnancies: possible role of human chorionic gonadotrophin
on ectopic pregnancy. American Journal of Pathology 163,
2211–2219.
Niklaus AL, Pollard JW 2006 Mining the mouse transcriptome of
receptive endometrium reveals distinct molecular signatures for
the luminal and glandular epithelium. Endocrinology April 20;
[Epub ahead of print].
Park KR, Inoue T, Ueda M et al. 2000 CD9 is expressed on human
endometrial epithelial cells in association with integrins alpha(6),
alpha(3) and beta(1). Molecular Human Reproduction 6, 252–257.
Ponnampalam AP, Weston GC, Trajstman AC et al. 2004 Molecular
classification of human endometrial cycle stages by transcriptional
profiling. Molecular Human Reproduction 10, 879–893.
Quenby S, Vince G, Farquharson R, Aplin J 2002 Recurrent
miscarriage: a defect in nature’s quality control? Human
Reproduction 17 1959–1963.
Regimbald LH, Pilarski LM, Longenecker BM et al. 1996 The
breast mucin MUCI as a novel adhesion ligand for endothelial
intercellular adhesion molecule 1 in breast cancer. Cancer
Research 56, 4244–4249.

Seif MW, Aplin JD 1990 Cell surface components of human
endometrial epithelium: monoclonal antibody studies. Trophoblast
Research 4, 339–356.
Talbi S, Hamilton AE, Vo KC et al. 2006 Molecular phenotyping of
human endometrium distinguishes menstrual cycle phases and
underlying biological processes in normo-ovulatory women.
Endocrinology 147, 1097–1121.
Thathiah A, Carson DD 2004 MT1-MMP mediates MUC1 shedding
independent of TACE/ADAM17. Biochemical Journal 382,
363–373.
Thathiah A, Blobel CP, Carson DD 2003 Tumor necrosis factor-alpha
converting enzyme/ADAM 17 mediates MUC1 shedding. Journal
of Biological Chemistry 278, 3386–3394.
Wynne F, Ball M, McLellan AS et al. 2006 Mouse pregnancy-
specific glycoproteins: tissue-specific expression and evidence of
association with maternal vasculature. Reproduction 131, 721–732.
Xiao LJ, Chang H, Ding NZ et al. 2002a Basigin expression and
hormonal regulation in mouse uterus during the peri-implantation
period. Molecular Reproductive Development 63, 47–54.
Outlook - Molecular mechanism of embryo implantation - JD Aplin
Xiao LJ, Diao HL, Ma XH et al. 2002b Basigin expression and
hormonal regulation in the rat uterus during the peri-implantation
period. Reproduction 124, 219–225.
Zhou XL, Lei ZM, Rao CV 1999 Treatment of human endometrial
gland epithelial cells with chorionic gonadotropin/luteinizing
hormone increases the expression of the cyclooxygenase-2 gene.
Journal of Clinical Endocrinology and Metabolism 84, 3364–
3377.
Paper based on contribution presented at the International
Serono Symposium ‘Human implantation: the new frontiers
of human assisted reproductive technologies’ in Erice, Sicily,
Italy, May 5–6, 2006.
Received 7 June, 2006; refereed 14 July, 2006; accepted 25 August,
2006.
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