Báo cáo khoa học: Signaling pathways and preimplantation development of mammalian embryos potx

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-

works, and any disruption to these networks may lead
to abnormal development or fatal disease.
Although there is a reasonably sound understanding
of the specific events associated with mammalian pre-
implantation embryo development, including activation
of the zygotic genome, development of the anterior–
posterior axis, compaction, and blastocyst formation,
little is known about the intracellular signaling path-
ways that regulate these events [1–6]. Several signal-
transduction pathways have been shown to be involved
Keywords
development; preimplantation embryo;
signaling pathways; signaling transduction
network; stage-specific expression pattern
Correspondence
J. Wu, School of Life Science and
Biotechnology, Shanghai Jiao Tong
University, no. 800, Dongchuan Road,
Minhang District, Shanghai, 200240, China
Fax: 86 21 3420 4051
Tel: 86 21 3420 4933
E-mail:
(Received 17 April 2007, revised 12 June
2007, accepted 5 July 2007)
doi:10.1111/j.1742-4658.2007.05980.x
The mammalian preimplantation embryo is a critical and unique stage in
embryonic development. This stage includes a series of crucial events: the
transition from oocyte to embryo, the first cell divisions, and the establish-
ment of cellular contacts. These events are regulated by multiple signal-
transduction pathways. In this article we describe patterns of stage-specific

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.

Stage-specific expression pattern of
several signal-transduction pathways
in the preimplantation embryo
We review the existing evidence for the presence of
each signaling pathway during preimplantation embryo
development, and summarize the stage-specific expres-
sion pattern of each signaling pathway (Fig. 1).
MAPK pathways
MAPK pathways transmit signals from ligand–receptor
interactions and convert them into a variety of cellular
responses, ranging from apoptosis to immune responses,
as well as proliferation, differentiation, growth and
embryonic development. The MAPK superfamily of
proteins can be subdivided into four separate signaling
cascades: extracellular signal-regulated protein kinase
(ERK), Jun N-terminal kinase (JNK), p38 and ERK5
or big MAP kinase 1 pathway [16–19]. All are highly
conserved throughout eukaryotic systems. Preimplanta-
tion embryos utilize MAPK pathways to relay signals
from the external environment in order to prepare
appropriate responses and adaptations to a changing
milieu. It is therefore important to figure out the roles
of MAPK pathways during preimplantation embryo
development.
Using RT-PCR and immunostaining, 10 transcripts
of MAPK signaling pathway members have been
detected in unfertilized eggs and ⁄ or zygotes. These
genes include SOS1 (Son of sevenless 1), RSK1 (ribo-
somal S6 kinase 1) and MAPK ⁄ ERK2, the expression
of which is lowest in unfertilized eggs; RSK3 and

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

MAPK/ERK5, RSK3
STAT5
JAK-STAT
Fig. 1. Stage-specific expression of several signal-transduction pathways in the preimplantation development of the mammalian embryo.
Red, Wnt signaling pathway; blue, Notch signaling pathway; green, BMP signaling pathway; yellow, PtdIns3K signaling pathway; gray,
JAK-STAT signaling pathway.
Signaling pathways in preimplantation development Y. Zhang et al.
4350 FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS
Raf1, Rafb, MEK (MAPK or ERK kinase)-1, -2, -5,
and MAPK ⁄ ERK1 are detected in unfertilized eggs
and blastocysts. Transcripts and the protein localiza-
tion of p38-regulated and -activated kinase, p38
MAPK, MK2 and hsp25 have also been observed
throughout murine preimplantation embryo develop-
ment. These proteins have been detected in tropho-
blasts on embryonic day (E)3.5, when they mediate
mitogenic fibroblast growth factor signals from the
embryo or colony-stimulating factor-1 signals from
the uterus [8,20]. The phosphorylation state and
position of the phosphoproteins in the cells suggest
that they might function in mediating mitogenic
signals.
Raf1 is expressed abundantly in unfertilized eggs
and throughout preimplantation embryo development.
Expression of MEK-1, -2, -5, and MAPK ⁄ ERK1 is
lowest in unfertilized eggs, and gradually increases
throughout the blastocyst stage. SOS1 and GAB1 are
also expressed at a low level in unfertilized eggs, but at
the beginning of the two-cell stage expression abruptly
increases and continues throughout preimplantation

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

[24].
Wnt signaling pathway
The Wnt signaling pathway consists of 19 Wnt genes
encoding secreted proteins [25], 10 Wnt receptors
composed of Frizzled genes, and low-density lipopro-
tein receptor-related protein (LRP) 5–6 as coreceptors
participating in signal transmission [26]. Antagonists
of Wnt signals include two categories [27]. Fzb
(frizzled-b) with its four homologs forms the secreted
frizzle-related protein (Sfrp) family, which can block
activation of the receptor through binding to Wnt
proteins directly [28]. Dickkopf-1 (Dkk1) and its three
homologs can bind to and inactivate the LRP core-
ceptors [29–31]. There are several intracellular compo-
nents of the Wnt signal-transduction pathway. The
canonical Wnt pathway (b-catenin pathway) is the
best characterized, and includes a series of phospho-
rylation reactions that eventually activate target genes
in the nucleus. Signal pathways triggered by Wnts
(Wnt1, -2, -2b, -3, -3a, -6, -7b, -8a and -8b) belong
to this phosphorylation mechanism. The signal-trans-
duction pathway activated by other Wnts (Wnt4, -5a,
and -11) is regulated by noncanonical pathways
involving the intracellular signaling cascade of Ca
2+
or JNK.
b-Catenin is present in the eggs and early embryos
of some vertebrate species; it is the first essential com-
ponent of the signal-transduction pathway that leads
to formation of the endogenous dorsal–ventral axis.

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

cell determination in preimplantation embryos.
Recently, the expression patterns of several Wnts
during preimplantation stages have been reported,
and mRNAs encoding for Wnt1, -2b, -3, -3a, -4, -5a,
-5b, -6, -7a, -7b, -10b and -11 have been described
[7,8,34]. Transcripts of Wnt3a, -6, -7b, -9a and -10b
have been detected in blastocysts, and Wnt1 and -4,
Sfrp1 and Dkk1 are highly expressed at this stage
[37]. Receptors (Fz2, frizzled-2 and Fz4, frizzled-4),
intracellular signal transducers and modifiers [Dishev-
elled (Dsh), adenomatous polyposis coli (APC), axin],
as well as nuclear effectors (e.g. homologs of Dro-
sophila arm, Tcf and groucho) are also present in
blastocysts [8]. Transcripts of Wnt3a are found at the
2-cell stage, decreased at the 4- ⁄ 8-cell stages, and are
strongly expressed in compact 8- and 16-cell and
early blastocysts. The source of the Wnt3a transcripts
in 2-cell embryos, i.e. whether of maternal or embry-
onic origin, is not clear, because the major gene
expression transition from the maternal to zygotic
stage occurs in the late two-cell embryo [38]. The
onset of expression of Wnt4 is observed in the 4- ⁄ 8-
cell stages, and is more strongly expressed at the
8- and 16-cell and blastocyst stages. Both Wnt3a and
-4 transcripts have been detected in some precompact
4- ⁄ 8-cell stages, with consistent expression detected in
all compact 8- and 16-cell and blastocyst stages [8].
Primers specific for Wnt11 amplified the expected size
product at the blastocyst stage, as well as in 10-week
whole fetus libraries during human preimplantation

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].

Class 1A PtdIns3Ks are activated through binding
of the Src homology (SH2) domain in the adaptor sub-
unit to autophosphorylated tyrosine kinase receptors,
or to nonreceptor tyrosine kinases in the cytoplasm,
such as the Src family kinases or JAK kinases. Activa-
tion of class 1B kinases occurs in the binding of
the catalytic subunit to heterotrimeric GTP-binding
proteins or G proteins. Activated PtdIns3Ks pre-
ferentially phosphorylate phosphatidylinositol-4,5-di-
phosphate (PtdIns-4,5-P
2
) in vivo, to produce
phosphatidylinositol 3,4,5 triphosphate (PtdIns-3,4,5-
P
3
) [42]. In turn, the production of PtdIns-3,4,5-P
3
is
regulated by the phosphates phosphatase and tensin
homolog deleted on chromosome 10 which catalyzes
the dephosphorylation of PtdIns-3,4,5-P
3
to PtdIns-
4,5-P
2
[44,45]. A wide variety of signal-transduction
proteins, including Akt, interact with PtdIns3K-gener-
ated phosphorylated phosphoinositides via lipid-bind-
ing pleckstrin homology domains [46]. This facilitates
recruitment of these proteins to the plasma membrane

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-

tus. Inhibition of Akt activity has significant effects on
the normal physiology of the blastocyst. Specifically,
inhibition of this pathway results in a reduction in
insulin-stimulated glucose uptake. Moreover, inhibiting
Akt activity can cause a significant delay in blastocyst
hatching, a developmental step facilitating implanta-
tion. Taken together, these data demonstrate the pres-
ence and function of the PtdIns3K ⁄ Akt pathway in
mammalian preimplantation embryos. These results
further our knowledge of the PtdIns3K ⁄ Akt signaling
pathway [13].
The Notch signaling pathway
The Notch signaling pathway is evolutionarily con-
served, and it is essential for cell fate decisions in many
different tissues in multicellular organisms. The data
show that the Notch signaling pathway blocks differ-
entiation towards a primary differentiation fate in a
cell, rather than directing the cell to a second, alterna-
tive differentiation program, or forcing the cell to
remain in an undifferentiated state [14,49–53].
Relatively few signal proteins are involved in the
function of the Notch signaling pathway, in which sig-
nals from the cell surface are conveyed to the nuclear
transcription machinery. The Notch receptor is synthe-
sized in the endoplasmic reticulum, undergoes matura-
tion in the trans-Golgi network, and is transferred to
the cell surface, where it interacts with ligands from
neighboring cells. This interaction occurs only when
cells are in physical contact with each other. The Notch
receptor is activated by this interaction and is prototyp-

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

cells. RT-PCR analysis shows the expression of STAT5
throughout preimplantation embryo development;
inhibiting the activation of JAK might interfere with
the localization of STAT5 to the nucleus, and reduce
the embryo development rate, suggesting that the
JAK–STAT5 signaling pathway has a key function in
preimplantation embryo development [55].
The BMP signaling pathway
BMPs are members of the TGF-b superfamily of
growth factors, which plays a critical role in develop-
mental and regenerative processes. BMPs were origi-
nally identified as regulators of bone formation in
rodents [56]. More than 30 BMPs have been identified
to date. BMPs are broadly conserved across the animal
kingdom, including vertebrates, arthropods and nema-
todes.
The BMPs fulfill their signaling function by binding
to a heterodimeric complex of two transmembrane
receptors, type 1 and type 2, which have serine–threo-
nine kinase activity [57–59]. When ligand binding is
required for type 1 receptor activation, the kinase
activity of the type 2 receptors is constitutive.
Although BMPs can bind to each of these weakly, and
subsequently recruit the second subunit, optimal ligand
binding is achieved when both type 1 and type 2 recep-
tors are present. The type 2 receptor transphosphory-
lates the type 1 receptor by ligand binding. The type 1
receptor then phosphorylates members of the Smad
family of transcription factors which are subsequently
translocated to the nucleus, activating the expression

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-

scripts may be from the embryonic genome. Therefore,
one- and two-cell stage embryos may have the ability
to respond to BMPs, either via an ActR-I ⁄ BMPR-II
receptor complex, or by forming a BMPR-IB ⁄ BMPR-
II receptor complex. Transcripts of BMPs have been
found in preimplantation embryos. However, some
researchers have detected several BMP proteins, mito-
tic arrest-deficient proteins, and other components of
the BMP signaling pathway, as well as homologs of
the receptors, in blastocysts, using cDNA microarray
analysis. BMP6, a member of the 60A subgroup of
BMPs, is expressed in diverse sites in the developing
mouse embryo from preimplantation onwards [8,64].
A profile of the signal transduction
network in the preimplantation
development of the mammalian embryo
All of the above-mentioned signaling pathways in pre-
implantation development are essential for various cell
events, such as cell proliferation, differentiation and
growth, as well as apoptosis, and interactions between
them have been established in many other types of
cells and biological processes, suggesting that there
exists a complex signal network controlling mamma-
lian preimplantation development.
SOX7 protein, one of the SRY box-containing tran-
scription factors (SOX proteins), can repress Wnt
signaling by inhibiting the ability of TGF ⁄ lymphoid
enhancer factor–b-catenin to transactivate a T-cell
factor ⁄ lymphoid enhancer factor-dependent reporter
construct [65]. Dickkopf-1 (Dkk1) is another potent

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].

The expression profiles of some genes that directly
or indirectly participate in the Notch signaling path-
way, including Notch1–4, Jag1–2, Dll-1, Rbpsuh and
Dtx1, have been observed in mammalian preimplanta-
tion embryos [9]. In other biological progresses, Notch
signaling has been suggested to repress the activity of
p38 MAPK by specifically inducing the expression of
MKP-1, a member of the dual-specificity MAPK phos-
phatase [75]. Notch negatively regulates the JNK path-
way by interfering with the interaction between JNK
and JNK-interacting protein 1 (JIP1) [76]. During
C. elegans vulval development, LIN-12 ⁄ NOTCH inac-
tivates MAPK to specify the secondary fate through
up-regulation of isoenzymes from Candida rugosa
lipase (LIP1) transcription [77]. Ras activation inter-
feres with endocytic routing of LIN-12, resulting in
downregulation of LIN-12 ⁄ Notch [78]. Whether the
interaction between the Notch and MAPK signaling
pathways similarly exists during preimplantation
Signaling pathways in preimplantation development Y. Zhang et al.
4354 FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS
embryo development needs to be clarified by further
research.
Some proto-oncogenes, including c-fos,c-jun,c-ha-
ras and c-myc, have been studied in bovine preim-
plantation blastocysts [79,80]. The c-fos,c-jun and
c-ha-ras transcripts, as well as c-Fos, c-Jun and
c-Myc proteins have been detected in 13–14-day-old
preimplantation blastocysts [80]. Wang et al. investi-
gated whether Ras mRNA is expressed in tropho-

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

regulative pattern of this transduction network. For
example, Wnt ⁄ b-catenin and BMP signal pathways
play a key role in the polarization of frog eggs [89,90].
In Xenopus, stabilization of b-catenin leads to the acti-
vation of dorsal-specific genes, while a member of the
Nodal family of TGF-b signals, Squint, serves as a
dorsal determinant in zebrafish embryos [91,92]. How-
ever, which part of this network is essential for trigger-
ing the first cell division and which is essential for the
first cell differentiation in preimplantation develop-
ment? These questions need further study. Moreover,
much more research is required on the whole signal-
transduction network in preimplantation embryo
development.
Perspectives
Preimplantation development is a unique and critical
stage during embryo development. It is not only the
very beginning of a new life, but also the beginning of
many biological reactions. Understanding the role of
signaling pathways in embryos is important for knowl-
edge about life processes. However, due to the diffi-
culties in manipulating preimplantation embryos,
progression in this field has been delayed, especially in
discovering how these signaling cascades function dur-
ing each particular event. To date, little of our knowl-
edge about these cascades has come from direct
experimental evidence, some has come from indirect
experimental observation, and much is speculation
based on the cascades functions in somatic cells. The
fact is that we still know little about this process, and

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

embryo development.STAT5 may regulate preimplantation develop-
ment by activating PtdIns3K. Ras may suppress c-Myc-induced
apoptosis by activation of the PtdIns3K ⁄ Akt pathway. Ras can
therefore stabilize the Myc protein, depending on the action of the
Raf ⁄ ERK pathway. Notch signaling represses the activity of p38
MAPK by specifically inducing the expression of MKP-1. Dvl pro-
teins are important transducers for the Wnt ⁄ b-catenin pathway.
Dvls can forms Wnt-induced complexes with Rac, and Rac can
induce JNK ⁄ MAPK signaling. Dkk1 and SOX7 are antagonists of
Wnt signaling. Both are identified as direct targets of the p38 and
JNK pathways.
Y. Zhang et al. Signaling pathways in preimplantation development
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4355
apoptosis, and explain why 15–50% of embryos die
during preimplantation development? Interactions
among these signaling pathways in somatic cells have
been reported elsewhere, and these complicated rela-
tionships construct a signaling network. Nonetheless,
specific interplay of these signal-transduction pathways
during this stage remains unclear. There are limited
experimental data for some of these questions, there-
fore further efforts should be made to enhance our
knowledge about the detailed molecular procedures of
the embryo preimplantation stage.
Acknowledgements
This work was supported by Key Program of National
Natural Scientific Foundation of China (No. 30630012)
and sponsored by Shanghai Pujiang Program, China
(No. 06PJ14058).
References

1 Memili E, Dominko T & First NL (1998) Onset of tran-
scription in bovine oocytes and preimplantation embryos.
Mol Reprod Dev 51, 36–41.
2 Schultz RM (1993) Regulation of zygotic gene activa-
tion in the mouse. Bioessays 15, 531–538.
3 Collins JE & Fleming TP (1995) Epithelial differentia-
tion in the mouse preimplantation embryo: making
adhesive cell contacts for the first time. Trends Biochem
Sci 20, 307–312.
4 Fleming TP, Ghassemifar MR & Sheth B (2000) Junc-
tional complexes in the early mammalian embryo. Semin
Reprod Med 18, 185–193.
5 Sutherland AE & Calarco-Gillam PG (1983) Analysis of
compaction in the preimplantation mouse embryo. Dev
Biol 100, 328–338.
6 Watson AJ & Barcroft LC (2001) Regulation of blasto-
cyst formation. Front Bio Sci 6, D708– D730.
7 Hamatani T, Carter MG, Sharov AA & Ko MS (2004)
Dynamics of global gene expression changes during
mouse preimplantation development. Dev Cell 6, 117–
131.
8 Wang QT, Piotrowska K, Ciemerych MA, Milenkovic
L, Scott MP, Davis RW & Zernicka-Goetz M (2004) A
genome-wide study of gene activity reveals developmen-
tal signaling pathways in the preimplantation mouse
embryo. Dev Cell 6, 133–144.
9 Cormier S, Vandormael-Pournin S, Babinet C &
Cohen-Tannoudji M (2004) Developmental expression
of the Notch signaling pathway genes during mouse
preimplantation development. Gene Expr Patterns 4,

713–717.
10 Schier AF (2001) Axis formation and patterning in
zebrafish. Curr Opin Genet Dev 11, 393–404.
11 Zernicka-Goetz M (2002) Patterning of the embryo.
The first spatial decisions in the life of a mouse. Devel-
opment 129, 815–829.
12 Ko MS, Kitchen JR, Wang X, Threat TA, Wang X,
Hasegawa A, Sun T, Grahovac MJ, Kargul GJ, Lim
MK et al. (2000) Large-scale cDNA analysis reveals
phased gene expression patterns during preimplantation
mouse development. Development 127 , 1737–1749.
13 Riley JK, Carayannopoulos MOH, Wyman A, Chi M,
Ratajczak CK & Moley KH (2005) The PI3K ⁄ Akt
pathway is present and functional in the preimplanta-
tion mouse embryo. Dev Biol 284, 377–386.
14 Hansson EM, Lendahl U & Chapman G (2004) Notch
signaling in development and disease. Semin Cancer Biol
14, 320–328.
15 Cadigan KM & Nusse R (1997) Wnt signaling: a com-
mon theme in animal development. Genes Dev 11, 3286–
3305.
16 Marshall CJ (1995) Specificity of receptor tyrosine
kinase signaling: transient versus sustained extracellular
signal-regulated kinase activation. Cell 80, 179–185.
17 Schaeffer HJ & Weber MJ (1999) Mitogen activated
protein kinases: specific messages from ubiquitous mes-
sengers. Mol Cell Biol 19, 2435–2444.
18 Ahn NG, Seger R & Krebs EG (1992) The mitogen-
activated protein kinase activator.
Curr Opin Cell Biol

4, 992–999.
19 Ono K & Han J (2000) The p38 signal transduction
pathway: activation and function. Cell Signal 12, 1–13.
20 Natale DR, Paliga AJ, Beier F, D’Souza SJ & Watson
AJ (2004) p38 MAPK signaling during murine preim-
plantation development. Dev Biol 268, 76–88.
21 Wang Y, Wang F, Sun T, Trostinskaia A, Wygle D,
Puscheck E & Rappolee DA (2004) Entire mitogen acti-
vated protein kinase (MAPK) pathway is present in pre-
implantation mouse embryos. Dev Dyn 231, 72–87.
22 Paliga AJ, Natale DR & Watson AJ (2005) p38 mito-
gen-activated protein kinase (MAPK) first regulates fila-
mentous actin at the 8–16-cell stage during
preimplantation development. Biol Cell 97, 629–640.
23 Maekawa M, Yamamoto T, Tanoue T, Yuasa Y, Chi-
saka O & Nishida E (2005) Requirement of the MAP
kinase signaling pathways for mouse preimplantation
development. Development 132, 1773–1783.
24 Xie Y, Wang Y, Sun T, Wang F, Trostinskaia A, Pus-
check E & Rappolee DA (2005) Six post-implantation
lethal knockouts of genes for lipophilic MAPK pathway
proteins are expressed in preimplantation mouse
embryos and trophoblast stem cells. Mol Reprod Dev
71, 1–11.
25 Miller JR (2001) The Wnts. Genome Biol 3, REVIEWS
3001. Epub 2001 December 28.
26 Seto ES & Bellen HJ (2004) The ins and outs of Wing-
less signaling. Trends Cell Biol 14 , 45–53.
Signaling pathways in preimplantation development Y. Zhang et al.
4356 FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS

27 Kawano Y & Kypta R (2003) Secreted antagonists of
the Wnt signalling pathway. J Cell Sci 116, 2627–2634.
28 Leyns L, Bouwmeester T, Kim SH, Piccolo S & De
Robertis EM (1997) Frzb-1 is a secreted antagonist of
Wnt signaling expressed in the Spemann organizer. Cell
88, 747–756.
29 Glinka A, Wu W, Delius H, Monaghan AP, Blumen-
stock C & Niehrs C (1998) Dickkopf-1 is a member of
a new family of secreted proteins and functions in head
induction. Nature 391, 357–362.
30 Brott BK & Sokol SY (2002) Regulation of Wnt ⁄ LRP
signaling by distinct domains of Dickkopf proteins. Mol
Cell Biol 22, 6100–6110.
31 Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos
PM, Smith JC & Krumlauf R (2003) Wise, a context-
dependent activator and inhibitor of Wnt signalling.
Development 130, 4295–4305.
32 Pauken CM & Capco DG (1999) Regulation of cell
adhesion during embryonic compaction of mammalian
embryos: roles for PKC and beta-catenin. Mol Reprod
Dev 54, 135–144.
33 Rogers I & Varmuza S (2000) LiCl disrupts axial
development in mouse but does not act through the
beta-catenin ⁄ Lef-1 pathway. Mol Reprod Dev 55, 387–
392.
34 Mohamed OA, Clarke HJ & Dufort D (2004) Beta-cate-
nin signaling marks the prospective site of primitive
streak formation in the mouse embryo. Dev Dyn 231,
416–424.
35 Van Noort M, Meeldijk J, van der Zee R, Destree O &

Clevers H (2002) Wnt signaling controls the phosphory-
lation status of beta-catenin. J Biol Chem 277, 17901–
17905.
36 Lloyd S, Fleming TP & Collins JE (2003) Expression of
Wnt genes during mouse preimplantation development.
Gene Expr Patterns 3, 309–312.
37 Kemp C, Willems E, Abdo S, Lambiv L & Leyns L
(2005) Expression of all Wnt genes and their secreted
antagonists during mouse blastocyst and postimplanta-
tion development. Dev Dyn 233, 1064–1075.
38 Schultz RM (2002) The molecular foundations of the
maternal to zygotic transition in the preimplantation
embryo. Hum Reprod Update 8, 323–331.
39 Adjaye J, Bolton V & Monk M (1999) Developmental
expression of specific genes detected in high-quality
cDNA libraries from single human preimplantation
embryos. Gene 237, 373–383.
40 Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J,
Katso R, Driscoll PC, Woscholski R, Parker PJ &
Waterfield MD (2001) Synthesis and function of 3-phos-
phorylated inositol lipids. Annu Rev Biochem 70, 535–
602.
41 Vanhaesebroeck B & Alessi DR (2000) The PI3K–
PDK1 connection: more than just a road to PKB.
Biochem J 3, 561–576.
42 Cantrell DA (2001) Phosphoinositide 3-kinase signalling
pathways. J Cell Sci 114, 1439–1445.
43 Vanhaesebroeck B & Waterfield MD (1999) Signaling
by distinct classes of phosphoinositide 3-kinases. Exp
Cell Res 253, 239–254.

44 Maehama T & Dixon JE (1999) PTEN: a tumour sup-
pressor that functions as a phospholipid phosphatase.
Trends Cell Biol 9, 125–128.
45 Leslie NR & Downes CP (2002) PTEN: the down side
of PI 3-kinase signaling. Cell Signal 14, 285–195.
46 Bottomley MJ, Salim K & Panayotou G (1998) Phos-
pholipid-binding protein domains. Biochim Biophys Acta
1436, 165–183.
47 Staal SP (1987) Molecular cloning of the akt onco-
gene and its human homologues AKT1 and AKT2:
amplification of AKT1 in a primary human gastric
adenocarcinoma. Proc Natl Acad Sci USA 84, 5034–
5037.
48 Gross VS, Hess M & Cooper GM (2005) Mouse embry-
onic stem cells and preimplantation embryos require sig-
naling through the phosphatidylinositol 3-kinase
pathway to suppress apoptosis. Mol Reprod Dev 70,
324–332.
49 Artavanis-Tsakonas S, Rand MD & Lake RJ (1999)
Notch signaling: cell fate control and signal integration
in development. Science 284, 770–776.
50 Artavanis-Tsakonas S, Matsuno K & Fortini ME
(1995) Notch signaling. Science 268, 225–232.
51 Robey E (1997) Notch in vertebrates. Curr Opin Genet
Dev 7, 551–557.
52 Lendahl U (1998) A growing family of Notch ligands.
Bioessays 20, 103–107.
53 Weinmaster G (1998) Notch signaling: direct or what?
Curr Opin Genet Dev 8, 436–442.
54 Mumm JS & Kopan R (2000) Notch signaling: from the

outside in. Dev Biol 228, 151–165.
55 Nakasato M, Shirakura Y, Ooga M, Iwatsuki M, Ito
M, Kageyama S, Sakai S, Nagata M & Aoki F (2006)
Involvement of the STAT5 signaling pathway in the reg-
ulation of mouse preimplantation development. Biol
Reprod 75, 508–517.
56 Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whit-
ters MJ, Kriz RW, Hewick RM & Wang EA (1988)
Novel regulators of bone formation: molecular clones
and activities. Science 242, 1528–1534.
57 Hogan BL (1996) Bone morphogenetic proteins: multi-
functional regulators of vertebrate development. Genes
Dev 10, 1580–1594.
58 Kingsley DM (1994) The TGF-b superfamily:
new members, new receptors, and genetic tests of
function in different organisms. Genes Dev 8,
133–146.
59 Massague J & Weis-Garcia F (1996) Serine ⁄ threonine
kinase receptors: mediators of transforming growth fac-
tor beta family signals. Cancer Surv 27, 41–64.
Y. Zhang et al. Signaling pathways in preimplantation development
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4357
60 Heldin CH, Miyazono K & Ten Dijke P (1997) TGF-
beta signaling from cell membrane to nucleus through
SMAD proteins. Nature 390, 465–471.
61 Massague J (1998) TGF-beta signal transduction. Annu
Rev Biochem 67, 753–791.
62 Lyons KM, Pelton RW & Hogan BL (1989) Patterns of
expression of murine Vgr-1 and BMP-2a RNA suggest
that transforming growth factor-beta-like genes coordi-

nately regulate aspects of embryonic development.
Genes Dev 3, 1657–1668.
63 Flach G, Johnson MH, Braude PR, Taylor RA & Bol-
ton VN (1982) The transition from maternal to embry-
onic control in the 2-cell mouse embryo. EMBO J 1,
681–686.
64 Roelen BA, Goumans MJ, van Rooijen MA & Mum-
mery CL (1997) Differential expression of BMP recep-
tors in early mouse. Int J Dev Biol 41, 541–549.
65 Takash W, Canizares J, Bonneaud N, Poulat F, Mattei
MG, Jay P & Berta P (2001) SOX7 transcription factor:
sequence, chromosomal localization, expression, trans-
activation and interference with Wnt signaling. Nucleic
Acids Res 29, 4274–4283.
66 Mao B, Wu W, Li Y, Stannek P, Glinka A & Niehrs C
(2001) LDL-receptor-related protein 6 is a receptor for
Dickkopf proteins. Nature 411, 321–325.
67 Grotewold L & Ruther U (2002) The Wnt antagonist
dickkopf-1 is regulated by Bmp signaling and c-Jun and
modulates programmed cell death. EMBO J 21, 966–975.
68 Wharton KA Jr (2003) Runnin¢ with the Dvl: proteins
that associate with Dsh ⁄ Dvl and their significance to
Wnt signal transduction. Dev Biol 253, 1–17.
69 Weitzel HE, Illies MR, Byrum CA, Xu R, Wikramana-
yake AH & Ettensohn CA (2004) Differential stability
of beta-catenin along the animal–vegetal axis of the sea
urchin embryo mediated by disheveled. Development
131, 2947–2956.
70 Na J, Lykke-Andersen K, Torres Padilla ME & Zerni-
cka-Goetz M (2007) Dishevelled proteins regulate cell

adhesion in mouse blastocyst and serve to monitor
changes in Wnt signaling. Dev Biol 302, 40–49.
71 Boutros M, Paricio N, Strutt DI & Mlodzik M (1998)
Dishevelled activates JNK and discriminates between
JNK pathways in planar polarity and wingless signaling.
Cell 94, 109–118.
72 Habas R, Dawid IB & He X (2003) Coactivation of
Rac and Rho by Wnt ⁄ Frizzled signaling is required for
vertebrate gastrulation. Genes Dev 17, 295–309.
73 Rosso SB, Sussman D, Wynshaw-Boris A & Salinas PC
(2005) Wnt signaling through Dishevelled, Rac and
JNK regulates dendritic development. Nat Neurosci 8,
34–42.
74 Natale DR & Watson AJ (2002) Rac-1 and IQGAP are
potential regulators of E-cadherin–catenin interactions
during murine preimplantation development. Gene Expr
Patterns 2, 17–22.
75 Kondoh K, Sunadome K & Nishida E (2007) Notch
signaling suppresses p38 MAPK activity via induction
of MKP-1 in myogenesis. J Biol Chem 282, 3058–3065.
76 Kim JW, Kim MJ, Kim KJ, Yun HJ, Chae JS, Hwang
SG, Chang TS, Park HS, Lee KW, Han PL et al.
(2005) Notch interferes with the scaffold function of
JNK-interacting protein 1 to inhibit the JNK signaling
pathway. Proc Natl Acad Sci USA 102, 14308–14313.
77 Berset T, Hoier EF, Battu G, Canevascini S & Hajnal
A (2001) Notch inhibition of RAS signaling through
MAP kinase phosphatase LIP-1 during C. elegans vulval
development. Science 291, 1055–1058.
78 Shave DD & Greenwald I (2002) Endocytosis-mediated

downregulation of LIN-12 ⁄ Notch upon Ras activation
in Caenorhabditis elegans. Nature 420, 686–690.
79 Ahmad K & Naz RK (1993) Presence and possible role
of c-ras and nuclear (c-fos and c-jun) proto-oncogene
products in preimplantation embryonic development in
mice. Mol Reprod Dev 136, 297–306.
80 Tetens F, Kliem A, Tscheudschilsuren G, Navarrete
Santos A & Fischer B (2000) Expression of proto-onc-
ogenes in bovine preimplantation blastocysts. Anat
Embryol (Berl) 201, 349–355.
81 Cantley LC (2002) The phosphoinositide 3-kinase path-
way. Science 296, 1655–1657.
82 Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gil-
bert C, Coffer P, Downward J & Evan G (1997) Sup-
pression of c-Myc-induced apoptosis by Ras signalling
through PI(3)K and PKB. Nature 385, 544–548.
83 Sears R, Nuckolls F, Haura E, Taya Y, Tamai K &
Nevins JR (2000) Multiple Ras-dependent phosphoryla-
tion pathways regulate Myc protein stability. Genes Dev
14, 2501–2514.
84 Grandori C, Cowley SM, James LP & Eisenman RN
(2000) The Myc ⁄ Max ⁄ Mad network and the transcrip-
tional control of cell behavior. Annu Rev Cell Dev Biol
16, 653–699.
85 Sears R, Leone G, DeGregori J & Nevins JR (1999)
Ras enhances Myc protein stability. Mol Cell 3, 169–
179.
86 Santos SC, Lacronique V, Bouchaert I, Monni R, Ber-
nard O & Gisselbrecht S (2001) Gouilleux F. Constitu-
tively active STAT5 variants induce growth and survival

of hematopoietic cells through a PI 3-kinase ⁄ Akt depen-
dent pathway. Oncogene 20, 2080–2090.
87 Nyga R, Pecquet C, Harir N, Gu H, Dhennin-Duthille
I, Regnier A, Gouilleux-Gruart V, Lassoued K &
Gouilleux F (2005) Activated STAT5 proteins induce
activation of the PI 3-kinase ⁄ Akt and Ras ⁄ MAPK
pathways via the Gab2 scaffolding adapter. Biochem J
390, 359–366.
88 Nguyen MH, Ho JM, Beattie BK & Barber DL (2001)
TEL-JAK2 mediates constitutive activation of the phos-
phatidylinositol 3¢-kinase ⁄ protein kinase B signaling
pathway. J Biol Chem 276, 32704–32713.
Signaling pathways in preimplantation development Y. Zhang et al.
4358 FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS
89 Tao Q, Yokota C, Puck H, Kofron M, Birsoy B, Yan
D, Asashima M, Wylie CC, Lin X & Heasman J (2005)
Maternal wnt11 activates the canonical wnt signalling
pathway required for axis formation in Xenopus
embryos. Cell 120, 857–871.
90 Reversade B & De Robertis EM (2005) Regulation of
ADMP BMP2 ⁄ 4 ⁄ 7 at opposite embryonic poles
generates a self-regulating morphogenetic field. Cell 123,
1147–1160.
91 Gore AV, Maegawa S, Cheong A, Gilligan PC, Weinberg
ES & Sampath K (2005) The zebrafish dorsal axis is appar-
ent at the 4-cell stage. Nature 438 (7070), 1030–1035.
92 Weaver C & Kimelman D (2004) Move it or lose it: axis
specification in Xenopus. Development 131, 3491–3499.
Y. Zhang et al. Signaling pathways in preimplantation development
FEBS Journal 274 (2007) 4349–4359 ª 2007 The Authors Journal compilation ª 2007 FEBS 4359