REVIEW ARTICLE
Signaling pathways and preimplantation development
of mammalian embryos
Yong Zhang
1
, Zhaojuan Yang
1
and Ji Wu
1,2
1 School of Life Science and Biotechnology, Shanghai Jiao Tong University, China
2 Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Shanghai Jiao Tong University, China
An embryo is a stage in the development of plants,
invertebrate and vertebrate animals. Embryonic devel-
opment is a key event in the organism and is under
rigorous control. Preimplantation growth is one of the
early embryonic development processes, from a single-
cell zygote, to a morula, to a blastocyst. Furthermore,
preimplantation development is critical in establishing
a viable mammalian pregnancy. During this period,
the zygote initiates its first cell division and the first
lineage cell begins to differentiate into the inner cell
mass and the trophectoderm. These processes are com-
plex and are regulated by various cell-signaling path-
ways. Each signal-transduction pathway is primarily
responsible for one or several related biological pro-
cesses, such as cell division, growth, differentiation,
migration, apoptosis, transformation, immune response
and polarity. By combining several functions, such as
cross-linking and other interactions, these pathways
form a complicated signaling network. Successful
embryo development requires functional signaling net-

expression in several signal-transduction pathways and try to give a profile
of the signaling transduction network in preimplantation development of
mammalian embryo.
Abbreviations
BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; ERK, extracellular signal-regulated protein kinase; JAK,
Janus-activated kinase; JNK, Jun N-terminal kinase; LRP, lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase;
PtdIns3K, phosphatidylinositol 3-kinase; PtdIns-3,4,5-P
3
, phosphatidylinositol-3,4,5-triphosphate; PtdIns-4,5-P
2
, phosphatidylinositol-
4,5-diphosphate; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; Wnt, Wingless.
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4349
in this process, including mitogen-activated pro-
tein kinase (MAPK), phosphatidylinositol 3-kinase
(PtdIns3K) ⁄ Akt, Wingless (Wnt) ⁄ b-catenin, Notch,
bone morphogenetic protein (BMP)–Smad, transform-
ing growth factor (TGF)-b, Hedgehog, and Janus-acti-
vated kinase (JAK) ⁄ signal transducer and activator of
transcription (STAT) signaling pathways. Moreover,
these signaling pathways play a central role in the
embryonic development processes of other vertebrate
and invertebrate animals [7–13].
Detailed mechanisms of these signaling pathways are
now better understood, and most have been reviewed
previously [14,15]. This article describes the patterns of
stage-specific expression of several signal-transduction
pathways and the signaling transduction network in
the preimplantation development of the mammalian
embryo.

MAPK ⁄ ERK5 are expressed at extremely low levels
in blastocysts; and GAB1 (Grb2-associated binder 1)
Zygote
2-Cell
4-Cell 8-Cell
Oocyte
16-Cell
32-Cell
Blastocyst
Marula Stage
Wnt
Wnt-4
Wnt-3a
Notch
Notch-1, Notch-2, Jag-1, Jag-2, DII-3, Rbpshu, Dtx-2
BMPR-II
Notch-3, DII-1, Dtx-1
BMP
ActR-1
BMRP-1B
PtdIns3K
Akt
80Kda and 110Kda subunit of PtdIns3K
BMRP-1A
Notch-4, DII-4
MAPK
Raf1
MEK-1, MEK-2, MEK-5, MAPK/ERK1
SOS1, GAB1
MAPK/ERK2

embryo development. MAPK ⁄ ERK2 could not be detec-
ted in unfertilized eggs but was detected at the two-cell
stage; it also increased throughout preimplantation
embryo development. This is in accordance with
activation of the zygotic genome. MAPK ⁄ ERK5 and
RSK3 mRNA was abundantly and increasingly
detected in unfertilized eggs up to the eight-cell ⁄ com-
paction stage, but was not detectable at the blastocyst
stage [21,22].
According to some experimental results, the JNK or
p38 MAPK pathway is required for development from
the 8–16-cell stage to the blastocyst stage, and p38
MAPK is a regulator of filamentous actin during
preimplantation embryo development [22]. Active
JNK and p38 MAPK pathways are required for cavity
formation during mouse preimplantation embryo
development, because inhibition of such signaling
pathways, excluding the ERK pathway, inhibits cavity
formation [23]. Maternal RNA of fibroblast growth
factor receptor substrate 2 (FRS2alpha), GAB1,
growth factor receptor-bound protein 2(GRB2), SOS1,
Raf-B and Raf1 genes may delay the presence of the
lethal phenotype of null mutations. These genes are
considered to be postimplantation lethal knockouts of
the genes for lipophilic MAPK pathway proteins.
They are all expressed at the protein level in the cyto-
plasm or in the cell membrane of E3.5 embryos, at
a time when the first known mitogenic intercellular
communication takes place. It is still not clear why the
lethality of these null mutants arises after implantation

Studies of immunoreactivity of total b-catenin in pre-
implantation embryos, from the two-cell stage to the
blastocyst stage, have shown that b-catenin accumu-
lates on the cell surface rather than in the nucleus [32–
34]. It has been shown that endogenous b-catenin
accumulates in the prospective dorsal side of the
embryo as early as the first division, and continues to
accumulate in the cytoplasm of all animal and vegetal
blastomeres, to a greater extent on the prospective dor-
sal side than on the ventral side, during the early
cleavage stages. By the 16- and 32-cell stages, b-catenin
accumulates in the dorsal but not the ventral nuclei
when zygotic transcription begins. The pattern of
b-catenin accumulation after cortical rotation thus
reflects the distribution of the transplantable dorsal-
determining activity. The nonphosphorylated isoform
of b-catenin accumulates in response to Wnt signaling
[35]. Recent studies have shown that b-catenin is neces-
sary and sufficient for formation of the dorsal axis,
and that it accumulates in cells that give rise to the
dorsal side of the embryo. These results indicate that
the Wnt ⁄ b-catenin signaling pathway is not active in
embryos until the blastocyst stage. They also show that
activation of the Wnt signaling pathway is sufficient to
Y. Zhang et al. Signaling pathways in preimplantation development
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4351
maintain the pluripotency of embryonic stem cells, and
that b-catenin is localized in the nuclei of the inner cell
mass, but not trophoblast cells in the blastocyst
[8,26,36]. This suggests that Wnts may participate in

embryo development [39]. These data suggest that
Wnts play a role in cell development and in cellu-
lar interactions occurring in preimplantation embryo
development.
By analyzing the expression levels of all 19 Wnt
genes and their 11 antagonists in mouse blastocysts,
pregastrula, gastrula and neurula stages, new expres-
sion domains for Wnt2b and Sfrp1 have been found
in the future primitive streak at the posterior side and
in the anterior visceral endoderm before the initiation
of gastrulation. Moreover, the anterior visceral endo-
derm expresses three secreted Wnt antagonists (Sfrp1,
Sfrp5 and Dkk1) in partially overlapping domains.
Notably, the predominant expression of Wnt1 and
Sfrp1 in the inner cell mass, and of Wnt9a in the
mural trophoblast and inner cell mass surrounding the
blastocele, suggests that the Wnt signal-transduction
pathway plays a novel role in preimplantation embryo
development.
The PtdIns3K/Akt signal transduction pathway
PtdIns3Ks consist of three types of enzymes, but they
can produce lipid secondary messengers by phosphory-
lation of plasma-membrane phosphoinositides at the
3¢OH group of the inositol ring [40]. Class 1
PtdIns3Ks include a catalytic subunit (110 kDa, p110)
and an adaptor ⁄ regulatory subunit. They can be sub-
grouped into class 1A and 1B PtdIns3Ks according to
their different catalytic subunits. Class 1B PtdIns3Ks
encompass a p110r catalytic subunit, associated with a
101 kDa (p101) adaptor subunit [40–43].

and their subsequent activation. Akt, a well-known
serine–threonine kinase mediator of survival signals is
the best characterized downstream target of PtdIns3K.
It is a central player in multiple signaling pathways,
and acts as a transducer of many functions initiated by
growth factor receptors that activate PtdIns3K [47].
The PtdIns3K ⁄ Akt signaling pathway is a major
pathway that has been found to regulate cell survival
downstream of activated growth-factor receptors. The
expression and function of this pathway have been
documented during early and late stages of the repro-
ductive process, including in murine preimplantation
embryos. PtdIns3K signaling is required to suppress
apoptosis in preimplantation embryos, because pro-
grammed cell death is rapidly induced by inhibition of
PtdIns3K with LY294002 [48]. Riley et al. [13] found,
using confocal immunofluorescence microscopy and
western blot analysis, that the p85 and p110 subunits
of PtdIns3K and Akt are expressed from the one-cell
stage through to the blastocyst stage of murine pre-
implantation embryo development. These proteins are
Signaling pathways in preimplantation development Y. Zhang et al.
4352 FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS
localized predominantly at the cell surface at the one-
cell stage through to the morula stage. Both PtdIns3K
and Akt exhibit an apical staining pattern in trophec-
toderm cells at the blastocyst stage. Phosphorylated
Akt was determined throughout murine preimplanta-
tion embryo development, and its presence at the
plasma membrane is a reflection of its activation sta-

ically cleaved, releasing the Notch intracellular domain
which translocates from the membrane to the nucleus,
where it interacts with the CSL DNA-binding protein
(CBF1 or Rbpsuh in vertebrates, suppressor of hairless
in Drosophila, Lag-1 in Caenorhabditis elegans) to regu-
late selected target gene expression [53,54]. The Notch
signaling pathway is modulated by numerous accessory
proteins, such as members of the Deltex family [50].
Cormier et al. [9] systematically examined the
expression profiles of genes that directly or indirectly
participate in the Notch signaling pathway in pre-
implantation embryo development. These include
Notch1–4, Jagged1–2 (Jag1–2), Delta-like1 (Dll-1),
Rbpsuh and Deltex1 (Dtx1). Notch1, -2, Jag1–2, Dll-3,
Rbpsuh and Dtx2 transcripts are synthesized in unfer-
tilized oocytes and at later blastocyst stages; Notch4
and Dll-4 mRNAs can be detected from the two-cell
stage to the hatched blastocyst stage; and Notch3, Dll-1
and Dtx1 mRNAs are found in two-cell embryos and in
hatched blastocysts, but are absent or present at a low
levels at the morula stage. These results suggest that
the Notch signaling pathway may be active during
these stages [9]. Using cDNA microarray technology,
researchers have also found that other genes of the
Notch pathway are expressed in the mouse embryo,
such as homologs of Drosophila N, Delta, deltex, fringe,
serrate and presenilin [8].
The JAK–STAT signaling pathway
The JAK–STAT5 signaling pathway plays a crucial
role in the growth and differentiation of mammalian

of target genes [60–62].
At the very beginning of the preimplantation stage,
embryonic polarity and spatial patterns start to
Y. Zhang et al. Signaling pathways in preimplantation development
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4353
develop [10,11]. BMP receptors (BMPRs) are essential
for this process, and BMPs exert their function by
binding to BMPRs. In the preimplantation mouse
embryo, large-scale cDNA analysis has been per-
formed and has provided some insight into the phased
gene expression patterns [12]. Activation of the Xeno-
pus BMP signaling pathway is coincident with the
onset of zygotic transcription, but requires maternal
signaling proteins. Analysis of the expression profiles
of several BMPRs has shown that BMPR-II mRNAs
are present in the zygote, two-cell and blastocyst
stages. However, no BMPR-II mRNA can be detected
at the four-cell and morula stages. Expression of
ActR-I one of the BMPR-Is, similar to BMPR-II, can
be observed at the zygote, two- and four-cell, and late
blastocyst stages, but not at the uncompacted or com-
pacted morula stages. BMPR-IA mRNA is detected
only in blastocysts; BMPR-IB transcripts are found at
all stages from the zygote to the uncompacted morula,
but are absent from the compacted morula and blast-
ocysts. Because maternal gene products are degraded
rapidly after the start of zygotic transcription [63],
transcripts of BMPR-IB at the one- and two-cell stages
are probably maternal derivations. However, at the
four-cell and uncompacted morula stages, the tran-

antagonist of Wnt signaling [29]. It specifically blocks
Wnt ⁄ b-catenin signaling by interacting with low-den-
sity lipoprotein receptor-related protein 6 [66]. Its
expression is regulated by the Ap-1 family member
c-Jun and it is activated by BMP-4 to induce apoptosis
[67]. Both Dkk1 and SOX7 have been identified during
mouse preimplantation embryo development as direct
targets of the p38 and JNK pathways [23]. Inhibition
of the p38 or JNK pathway leads to decreased expres-
sion of Dkk1 and SOX7 [23].
Dishevelled (Dsh ⁄ Dvl) proteins are important trans-
ducers for divergent Wnt pathways that lead to
different cell events: cell proliferation, apoptosis, or
differentiation [68,69]. Recently, this type of protein
has been identified in mouse oocytes and during preim-
plantation embryo development, and has an important
function in the regulation of cell adhesion in mouse
blastocysts [70]. The changes in expression of Dvl pro-
teins are coincident with those of b-catenin and p120
catenin transcription during preimplantation embryo
development, implying upregulation of Wnt signaling
activity before implantation [70]. Furthermore, Dvls
can induce JNK MAPK signaling [71–73]. The reason
might be that Dvl can form Wnt-induced complexes
with Rac and Rho, and Rac stimulates JNK activity
independent of Rho [72,73]. Rac-1 protein has been
demonstrated throughout murine preimplantation
embryo development and is a potential regulator of
E-cadherin ⁄ catenin interactions during this develop-
ment progress [74].

blasts in E3.5 embryos [61]. The PtdIns3K ⁄ Akt
signaling pathway, which is a major pathway for reg-
ulating cell survival downstream of activated growth
factor receptors [81], has also been demonstrated
throughout murine preimplantation embryo develop-
ment [13]. The proto-oncogene Ras may suppress
c-Myc-induced apoptosis, via activation of the PtdIns3-
K ⁄ Akt pathway [82]. Sears et al. [83] found that Ras
can control Myc protein (a regulator of the cell cycle
and essential for cell growth) accumulation via the
PtdIns3K ⁄ Akt pathway by downregulating the kinase
GSK-3 that promotes Myc degradation. However,
Ras regulates the accumulation of Myc activity by
stabilizing the Myc protein [84], depending on the
action of the Raf ⁄ ERK pathway [85]. Furthermore,
STAT5 has been identified throughout preimplantation
embryo development using RT-PCR [55]. It has been
shown that STAT5 may induce cell proliferation by
activating PtdIns3K, by interacting with p85 and
Grb2-associated binder-2 (Gab2) [86,87]. Nyga et al.
have found that Gab2 seems to activate ERK1 ⁄ 2 via
PtdIns3K in Ba ⁄ F3 cells that express constitutively
activated STAT5 [87]. TEL-JAK2 can constitutively
activate the PtdIns3K signaling pathway independent
of the STAT5 pathway [88].
This illustrates the complex interactions among these
signaling pathways during mammalian preimplantation
embryo development (Fig. 2), even if it is just a profile
of the signaling network. In different preimplantation
events and different species, there should be a different

dozens of questions remain unanswered, such as which
signaling pathway triggers the activation of the zygote
genome? Is it exogenous or endogenous? What is the
exact means of maternal signaling proteins passing on
new life? Which signaling cascade participates in cavity
formation during development of the blastocyst?
Which cascades participate in preimplantation embryo
JAKs
Ras
STAT5
PI3K
AKT
Myc
Cell Growth
division, apoptosis
differentiation
SOX7
c-Jun
Dkk1
Bmp-4
DvI
Raf
MKP-1
Notch
Wnt
Rac
ERK p38 JNK
active repress
directly indirectly
Fig. 2. Signal network predicted during mammalian preimplantation

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