Diﬀerentiation (2005) 73:1–17
r International Society of Diﬀerentiation 2005
R E V IE W
Jia L. Song . Gary M. Wessel
How to make an egg: transcriptional regulation in oocytes
Received October 14, 2004; accepted October 17, 2004
Abstract The oocyte is a highly differentiated cell. It
makes organelles specialized to its unique functions and
progresses through a series of developmental stages to
acquire a fertilization competent phenotype. This review will integrate the biology of the oocyte with what is
known about oocyte-specific gene regulation and transcription factors involved in oocyte development. We
propose that oogenesis is reliant on a dynamic gene
regulatory network that includes oocyte-specific transcriptional regulators.
Key words oogenesis primordial germ cells oocytes gonadal development transcriptional
regulation
Introduction
An oocyte must undergo several developmental transitions during which it acquires a specialized extracellular
matrix and synthesizes a unique set of proteins in order
to become a fertilizable egg. The making of an egg is
dictated by networks of oocyte-specific gene expression
patterns that are at least in part regulated by transcriptional mechanisms discussed in this review. Little is
known about the transcriptional proﬁle within an
oocyte and how oocyte-specific genes are regulated
throughout the lifetime of an egg.
Development of the egg begins with the formation of
primordial germ cells (PGCs) in the embryo and is followed by oogonial proliferation by mitosis, and initiation of meiosis I as primary oocytes. Oocytes may be
. )
Jia L. Song Gary M. Wessel (*
Department of Molecular and Cell Biology and Biochemistry
Brown University
69 Brown Street
Box G-J4
Providence, RI 02912
USA
Tel: 11 401 863 1051
Fax: 11 401 863 1182
E-mail: [email protected]
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arrested in the ﬁrst prophase of meiosis from 12–50
years in humans, up to 3 years in frogs, and up to a year
for most echinoderms. In response to various signals
from gonadal somatic cells, the primary oocytes then
grow, differentiate, and meiotically mature. Throughout the development of the oocyte, or oogenesis, the
oocyte must make all the necessary maternal factors in
preparation for fertilization. A hallmark of the oocyte
across many species is its high level of transcription,
reﬂecting the importance of maternal mRNAs and proteins that are crucial for supporting not only the growth
of the oocyte, but the newly fertilized zygote as well
(Smith and Richter, 1985; Davidson, 1986; Wassarman
and Kinloch, 1992). The complexity and careful regulation of the transcriptional activity of the oocyte
dictate its ultimate acquisition of developmental competence. This review will combine data and models from
diverse oocyte types to emphasize our current knowledge of oocyte transcriptional regulation and transcription factors that play a role in the regulation of oocyte
development.
Biology of the oocyte
An oocyte is a specialized cell whose differentiated phenotype supports fertilization and early development. In
addition to having vast numbers of organelles typical to
a eukaryotic cell such as the endoplasmic reticulum,
mitochondria, and the Golgi apparatus, it also possesses organelles unique to the oocyte functions. These include annulate lamellae, cortical granules, and yolk
granules (Lash and Whittaker, 1974; Wessel et al.,
2001). Each of these structures is made largely by the
oocyte and relies on oocyte-specific gene activity at high
levels. In addition, all animal eggs are surrounded by
one or more extracellular coats made specifically by the
oocyte (Dumont and Brummett, 1985).
The extracellular matrix of the oocyte plays a crucial
role in both fertilization and early development. Many
eggs of both vertebrate and invertebrate animals, such
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Fig. 1 Egg morphologies differ greatly throughout phylogeny, yet
each egg constructs an elaborate extracellular matrix involved in
both the fertilization process and in early development. Shown are
eggs representative of the bilaterian evolutionary branches, deuterostomes, ecdysozoans, and lophotrochozoans, and include the
following: a sea urchin (Lytechinus variegatus; echinoderm) egg in
the process of fertilization (A) DIC image, see lifting fertilization
envelope on the left) and (B) an SEM view of the vitelline layer
(Chandler and Heuser, 1980); (C) a pool of frog (Xenopus laevis,
amphibian) eggs, along side a quick-freeze, deep etched view of the
surface of a frog egg (D) showing the plasma membrane, the overlying vitelline layer, and a cortical granule immediately below the
plasma membrane (Larabell and Chandler, 1988); (E) a newly fer-
tilized ﬁsh embryo (Danio rerio), with its expanded chorion
(Kimmel et al., 1995) and (F) an inset of a SEM view of a fractured chorion at the sperm-entry point, the micropyle (Wolenski
and Hart, 1987); (G) a hamster egg (Mesocricetus auratus) embedded in its zona pellucida and cumulus mass shown by brightﬁeld
(Gilbert, 2000) and (H) an SEM view of the zona pellucida following removal of the cumulus cells (http://www.bioone.org/bio
one/?request=get-document&issn=0006-3363&volume=063&issue=
05&page=1437#ﬁgures); (I) the chorion of a ﬂy egg (Drosophila
melanogaster) shown by SEM (http://www.molbio.princeton.edu/
facility/confocal/SEM/IMAGELIST1.html); and (J) the surface of
a shrimp egg, shown by SEM, with sperm attached to its vitelline
layer apparent in the inset (K).
as frogs and sea urchins, are surrounded by an outer
jelly coat and an inner vitelline envelope (Fig. 1) (Wessel
et al., 2001). In contrast, ﬂies and ﬁsh are surrounded by
a tough chorion layer, whereas all mammalian eggs are
surrounded by a thick coat, called the zona pellucida
(ZP). The molecular composition of each of these extracellular coats appears distinct from each other; yet,
they are functionally analogous. In mammals and ﬁsh,
an extensive oocyte extracellular matrix is synthesized
during oogenesis prior to fertilization, and the contents
of the cortical granule, membrane-bound, stimulus-dependent secretory vesicles, further modify the extracellular matrix at fertilization (Fig. 1) (Wessel et al., 2001).
At the other extreme are frog and sea urchin oocytes
that have a minimal extracellular matrix but massive
secretions of cortical contents transform the extracellular matrix following fertilization.
The extracellular matrix of the egg contains specialized components that ensure proper binding and activation of the sperm. In sea urchins, a protective,
physical barrier for the developing oocyte is composed
of the egg jelly synthesized by somatic cells and contains
sperm chemoattractants and peptides (such as speract
and resact) that activate the sperm (Gilbert, 2000). Apposed to the plasma membrane of the egg is the vitelline
layer, which consists of a network of glycoproteins
(Dumont and Brummett, 1985). The main function of
the vitelline layer prior to fertilization is for sperm attachment but is sufﬁciently porous to allow the transfer
of macromolecules into the growing oocyte. The vitelline
3
Fig. 2 Cortical granules of two species of sea urchins shown by
transmission electron microscopy. (A) Stongylocentrotus purpuratus
cortical granules apposed to the plasma membrane of the egg contain a spiral lamellar, primo, substructure adjacent to a homogenous electron lucent region. The 15 nm gold particles are attached
to antibodies against SFE9, a structural protein destined for the
fertilization envelope, showing that proteins are specific to the
cortical granules and to only the spiral region. (B) Cortical granules
of Arbacia punctulata showing a distinct, stellate substructure, even
though the contents appear conserved between different sea urchin
species (Wong and Wessel, 2004). Scale bar 5 0.5 mm.
layer also serves as a scaffold for the attachment of
proteins released by the cortical granules at fertilization
in the formation of the fertilization envelope (reviewed
in Wessel et al., 2001). Molecules in the cortical granules
are specific to the oocyte and serve their function only
during fertilization (Fig. 2). So far, of the 12 cortical
granule proteins characterized in the sea urchin, all except two are the result of genes whose activities are
unique to the oocytes (Wessel et al., 2001; Wong and
Wessel, 2004).
The analogous extracellular structure in mammals,
the ZP, is formed during oogenesis and increases in
thickness as the oocyte grows. During fertilization,
sperm must bind to and penetrate the ZP in order to
fuse with the egg plasma membrane (reviewed in Wassarman et al., 2004). Following fertilization, the cortical
granule contents released by the oocyte modify the ZP
to block additional sperm penetration. In addition, the
ZP prevents the developing mammalian blastocyst from
adhering to the oviduct wall as it travels to the uterus.
The blastocyst embryo hatches from the ZP by using a
trypsin-like protease, strypsin, thus enabling implantation (Perona and Wassarman, 1986).
Another specialized family of proteins whose presence is dependent upon oocyte-specific gene activity is
the proteins associated with yolk acquisition and storage. Yolk proteins are the nutritional source for all nonplacental embryos and depending on the animal and the
protein, they can either be synthesized in various organs
of the adult and imported into the oocyte, or be syn-
thesized by the oocyte directly (reviewed in Brooks and
Wessel, 2003). In egg-laying species, oocytes contain
low-density lipoprotein receptors on their surface that
bind to yolk components such as vitellogenin and other
ligands and selectively transport them into oocytes via
receptor-mediated endocytosis (Schneider, 1996). Vitellogenin receptors have been identiﬁed in a wide range of
animals including insects, frogs, ﬁsh, and birds (Schneider, 1996; Sappington and Raikhel, 1998). In sea urchin oocytes, in addition to the proteins responsible for
the uptake of exogenously synthesized MYP (Major
Yolk Protein), the oocyte also synthesizes YP30 (Yolk
Platelet Protein of 30 KDa) (Wessel et al., 2000b;
Brooks and Wessel, 2003). YP30 is synthesized exclusively by sea urchin oocytes, is packaged selectively into
yolk platelets, and is hypothesized to function in the
packaging and storing of other yolk proteins during
oognesis. In other animals, including mollusks, polchaetes, and crustaceans, ultrastructural analyses suggest that yolk is also synthesized by the oocyte
(Eckelbarger, 1979; Zerbib, 1980; Kress, 1982; reviewed
in Brooks and Wessel, 2003). In order for the oocyte to
carry out its specialized functions, it likely requires a
unique repertoire of transcriptional strategies.
Following the transition from an oogonia, the developing oocyte generally increases its transcriptional activity, resulting in a stockpile of mRNA and proteins
that can be utilized quickly following fertilization and
embryogenesis (Smith and Richter, 1985; Davidson,
1986; Wassarman and Kinloch, 1992). The accumulation
4
of mRNAs by oocytes during its growth phase is crucial
to later development, and oocytes that have not completed their growth phase fail to develop properly as
embryos (Fair et al., 2004; reviewed in Fair, 2003).
Some gene products are only synthesized and utilized
during the life of the oocyte. For example, the RNA
transcripts of the ZP genes, which encode gene products
that make up the mammalian egg coat, increase markedly during mouse oogenesis and then decrease to undetectable levels prior to ovulation (Roller et al., 1989;
Epifano et al., 1995). Similarly, in sea urchins, oocytespecific genes involved in modiﬁcation of the extracellular matrix analogous to the ZP, such as Soft
Fertilization Envelope genes, SFE1, SFE9, and Ovoperoxidase (OPO), also increase in abundance during
oogenesis until oocyte maturation (Laidlaw and Wessel, 1994; LaFleur et al., 1998; Wessel et al., 2000a).
Each of these transcripts is then selectively degraded,
and their expression is repressed, so that these transcripts are not detectable following oocyte maturation.
Ovoperoxidase is an enzyme that catalyzes the covalent
tyrosine cross-linking of the structural proteins of the
envelope, SFE1 and SFE9. These structural proteins
modify the extracellular environment of the oocyte to
prevent polyspermy and are constructed promptly after
fertilization (LaFleur et al., 1998; Wessel et al., 2000a).
The transcript dynamics of YP30 is similar to that of
the SFE and OPO in that its mRNA is most abundant
in developing oocytes and is no longer detectable upon
oocyte maturation (Wessel et al., 2000b).
What makes the oocyte unique begins with the proper transcription of oocyte-specific genes. Numerous
studies have focused on the general biology of oocyte
development and meiotic regulation, but little is known
of the transcriptional regulatory mechanisms of oocytes. Is the transcriptional proﬁle within the oocyte
uniform throughout oogenesis or do transitions occur
indicative of a progressive transcriptional network? Are
oocyte-specific genes regulated by unique sets of regulatory proteins throughout oogenesis or does the cell
use master gene regulators?
Gametes develop from PGCs
Gametes develop from PGCs that are established during early embryogenesis. In the nematode Caenorhabditis elegans, the fruit ﬂy Drosophila
melanogaster, and the frog Xenopus laevis, PGCs originate from a morphologically distinct region of the zygote during early embryonic divisions (Fig. 3) (Ikenishi,
1998). In sea urchins and mammals, the PGCs appear to
be induced de novo from other cells in the early gastrulating embryo (Lawson and Hage, 1994; Ransick et al.,
1996; McLaren, 2003). PGCs have an extragonadal origin and navigate through various tissues to reach the
somatic gonad. Overall, the mechanisms of PGC migration are highly conserved in divergent animal classes
and involve intrinsic and somatic cues, attraction and
repulsion, and amoeboid motility (Matova and Cooley,
2001; McLaren, 2003; Raz, 2003).
Several molecules involved in the molecular mechanisms of germline establishment have been localized to
PGCs in different animal species. Some of these molecules are conserved germline determinants, such as
vasa, tudor, pumilio, nanos, germ cell less, and mago
nashi, while others appear species specific, such as oskar
in ﬂies and pgl-1 in worms (reviewed in Matova and
Cooley, 2001; Extavour and Akam, 2003). Most of
these germline factors are involved in translational regulation. Oct-4, however, is a maternally inherited transcription factor that is essential for the maintenance of
the mammalian germline (Pesce and Scholer, 2000;
Fuhrmann et al., 2001) (discussed below). Oct-4 is postulated to function as a transcriptional activator of
genes required in maintaining an undifferentiated totipotent state and may repress the transcription of lineage-specific regulatory genes. Once in the gonad, germ
cells begin to actively divide mitotically and become either oogonia or spermatogonia. In many invertebrate
and vertebrates, oogonia divide to form clusters of interconnected cells (Pepling et al., 1999; Matova and
Cooley, 2001). As the meiotic process is initiated,
oogonial germ cells are referred to as primary oocytes.
Primary oocytes undergo extreme growth, from 10 mm
up to several centimeters, depending on the animal, and
this growth involves bidirectional communication between the germ cells and the gonadal somatic cells (De
La Fuente and Eppig, 2001; Matzuk et al., 2002). The
somatic cells provide nutrients and secrete signals important for the growth of the oocyte. In Drosophila and
C. elegans, the oocyte develops in a syncytium (Gibert
et al., 1984; reviewed in Matova and Cooley, 2001). In
different vertebrates, including zebraﬁsh, Xenopus, chicken, and most mammals, clusters of oogonial cells undergo a growth phase within cysts (Ukeshima and
Fujimoto, 1991; Matova and Cooley, 2001; Raz, 2003).
The surface membranes of oocytes and their surrounding
granulosa cells in mice are connected by gap junctions,
which facilitate the transfer of glucose metabolites, amino acids, and nucleotides from the follicular cells to the
growing oocytes (Eppig, 1991; Wright et al., 2001).
Oocyte-secreted factors play key roles in the development and differentiation of ovarian follicles. Oocytespecific factors that inﬂuence follicular development
include proteins of the transforming growth factor b
superfamily members, growth differentiation factor
(GDF-9), and bone morphogenic protein (BMP-15)
(Dong et al., 1996; Yan et al., 2001). Mice lacking
GDF-9 are infertile because of a lack of follicular development, and mice lacking BMP-15 have decreased
ovulation and fertilization rates (Dong et al., 1996; Yan
et al., 2001). The bidirectional communication between
5
A
C. elegans
P1
egg
B
2-cell
zygote
16-cell embryo
Drosophila
egg
C
P4
cleavage embryo
syncytial blastoderm
embryo
Xenopus
blastocoel
animal
vegetal
Egg
D
Blastula
2-cell embryo
Chick
E
Mouse
germinal crescent
amniotic cavity
primitive streak
area pelluoida
anterior
primitive
streak
epiblast
area opaca
Fig. 3 Origin of PGCs. Germ plasm in (A–C) is shown in red;
PGCs in all panels are depicted in red as well. (A) Caenorhabditis
elegans P granules are distributed throughout the mature egg. They
are segregated away from the somatic lineage through a series of
unequal divisions that produces the P1 blastomere in the 2-cell
embryo and the germline founder, P4, in the 16-cell embryo. (B)
Drosophila pole plasm is localized at the posterior end of the mature egg. The early embryo undergoes synchronous nuclear divisions without cytokinesis. Nuclei that arrive at the posterior end of
the embryo are the ﬁrst to cellularize, thus forming pole cells that
include pole plasm. (C) Xenopus germinal plasm is localized to the
vegetal pole of the mature egg. It is partitioned equally between the
ﬁrst four blastomeres and ingresses along the cleavage planes. At
the blastula stage, germinal plasm is found in about 20 cells that are
positioned near the ﬂoor of the blastocoel. (D) Chick PGCs are ﬁrst
detected at the blastodisc stage. They are mostly found in a region
called the germinal crescent that is positioned anteriorly to the
embryo proper. (E) Mouse PGCs can be visualized at around day
7.5 postfertilization. They are found in the area of the epiblast that
is proximal to the primitive streak. Modiﬁed from Matova and
Cooley (2001).
the oocyte and follicle cells involves autocrine, paracrine, and endocrine regulations and ensures their
proper differentiation and development.
animals contain lampbrush chromosomes, readily
observed in the growing oocytes of organisms that produce large eggs. These chromatin loops of transcriptional activity were ﬁrst observed by Flemming (1882)
in urodele oocytes and examined in detail by Ruckert
(1892) in shark oocytes. In the 1960s, autoradiographic
studies carried out with the light microscope showed
that intense RNA synthesis occurs throughout the lateral loops of the lampbrush chromosomes (Gall and
Callan, 1962; Hill and Macgregor, 1980; Davidson,
1986). In large oocytes that contain excessive pools of
maternal RNA, lampbrush chromosomes reﬂect a maximal and continuous ﬂow of transcription products
Discovery of transcriptional activity in the
oocyte—a historical perspective
The study of transcriptional regulation has a deep history in oocytes. Even before the central dogma was
posed, structures within the oocyte nucleus were intensively investigated that led to our understanding of
transcriptional units. For example, the oocytes of many
6
throughout oogenesis (Smith and Richter, 1985; Davidson, 1986). Lampbrush chromosomes are not a prerequisite for the synthesis and accumulation of maternal
message though, because not all oocytes contain these
structures (Smith and Richter, 1985; Davidson, 1986).
Maternal RNAs were demonstrated in the 1930s and
are deﬁned as RNAs synthesized by the oocyte prior to
fertilization but utilized in early embryogenesis (reviewed in Davidson, 1986). In many species examined
(including echinoderms and amphibians), maternal
RNA has high complexity and is sufﬁcient to support
all the needed protein biosynthesis required during early
development (reviewed in Davidson, 1986). The timing
of activation of zygotic genes is species dependent and is
highly variable. For example, zygotic gene activation
occurs within minutes in sea urchins, at the two-cell
stage in mice, four- to eight-cell stage in cows and humans, eight- to 16-cell stage in sheep and rabbits, and
not until the mid-blastula transition in amphibians
(Schultz and Heyner, 1992). Prior to zygotic gene activation, the zygote is supported by maternal mRNAs
transcribed and translated during oogenesis.
First example of oocyte-specific gene regulation:
oocyte-type rRNA
In the early 1960s the bulk of the maternal RNA stored
in eggs was known to be rRNA (Davidson, 1986). The
store of maternal ribosomes inherited in the egg cytoplasm is sufﬁcient to support protein synthesis immediately following fertilization and in the ﬁrst few stages
of embryogenesis. The most thoroughly examined gene
regulation in the oocyte is the transcription of 5S RNA
genes (reviewed in Smith and Richter, 1985; Wolffe,
1994). Two types of 5S RNA genes exist in the Xenopus
oocyte: an ‘‘oocyte type’’ present in about 20,000 copies
and a ‘‘somatic type’’ present in about 400 copies per
haploid genome (Brown and Sugimoto, 1973; Ford and
Southern, 1973; Peterson et al., 1980). The regulation of
5S RNA was initially examined by a cell-free transcription system in which puriﬁed somatic 5S RNA gene
was observed to be transcribed in extracts from both
oocyte and unfertilized eggs, whereas oocyte 5S RNA
gene was only transcribed from the oocyte extract (reviewed in Wormington and Brown, 1983; Smith and
Richter, 1985).
The transcription of 5S RNA genes requires the general transcription factors TFIIIA, B, and C, and the 5S
RNA gene promoter lies within the gene itself (internal
control region (ICR)) (Fig. 4) (Wolffe, 1994). The
oocyte and somatic 5S RNA genes have a total of 5 bp
difference within the ICR, of which 3 bp are located
within the TFIIIC-binding site. This sequence variation
contributes to the preferential association of TFIIIC to
the somatic 5S RNA gene (Fig. 4) (Wolffe, 1988, 1994;
Fig. 4 The oocyte and somatic 5S RNA genes and the 5S RNA
gene transcription complex. (A) The oocyte (major variant) gene
family has a repeating unit of 650–850 bp and consists of a gene
(open arrow) and a pseudogene (open box) separated by an A1Trich spacer. The somatic gene family has a repeating unit of 880 bp
consisting of a gene (open arrow) and a G1C-rich spacer. (B, C)
Differential transcription factor association with oocyte and somatic 5S RNA genes inﬂuences transcription during development.
(B) TFIIIA and TFIIIC interactions with oocyte and somatic 5S
RNA genes. TFIIIA forms a specific complex with both oocyte and
somatic 5S RNA genes. Both of these complexes are unstable
(Kd 5 10–9 M). TFIIIC recognizes TFIIIA bound to both 5S
RNA genes, however, because of sequence differences at one of the
key contacts made by the protein (vertical arrows), TFIIIC does not
stabilize the TFIIIA/oocyte 5S DNA complex. Thus TFIIIA remains in free equilibrium with factors in solution (open arrowheads). In contrast, TFIIIC rapidly stabilizes TFIIIA association
with the somatic 5S RNA gene. (C) During oogenesis the excess of
TFIIIA (molecules per gene) is high, as embryogenesis proceeds
past the stage at which transcription is activated (the mid-blastula
transition, MBT) towards neurulation, this excess declines rapidly.
The transcriptional activity of oocyte and somatic 5S RNA genes at
these different stages is indicated. From Wolffe (1994).
Keller et al., 1990, 1992). TFIIIA forms a specific but
unstable complex with the 5S gene. TFIIIC recognizes
the TFIIIA/5S DNA complex and recruits TFIIIB,
which is then recognized by RNA polymerase III
(Bieker et al., 1985; Setzer and Brown, 1985; Kassavetis
et al., 1990). During oogenesis, the somatic and oocyte
5S RNA genes are transcribed with nearly the same
efﬁciency when TFIIIA is in excess (Wolffe, 1994). So
where is the transcriptional switch that distinguishes
somatic and oocyte 5S gene activities? Recent evidence
suggests that phosphorylation of Xenopus TFIIIA by
casein kinase II allows the factor to act as an activator
of the somatic 5S RNA and as a repressor of the oocytetype 5S RNA upon oocyte maturation (Ghose et al.,
7
2004). Phosphorylated TFIIIA binds to the promoters
of both the somatic and oocyte-type 5S RNA genes, but
it represses the transcription of the oocyte-type 5S RNA
selectively, possibly by interfering with protein–protein
interactions necessary for oocyte-type transcription
(Ghose et al., 2004).
An important mediator of 5S RNA gene transcription also involves changes in chromatin structure
(reviewed in Panetta et al., 1998; Crane-Robinson,
1999). The expression of linker histone protein (H1)
is developmentally regulated; in Xenopus it is translated
during early embryogenesis but not in oocytes (Wolffe,
1994; Panetta et al., 1998; Crane-Robinson, 1999).
In the presence of the histone H1, a stable nucleosome
is positioned on the oocyte 5S RNA gene that prevents binding of TFIIIA, whereas on the somatic
5S RNA gene, essential promoter elements remain accessible to TFIIIA (Bouvet et al., 1994; Panetta et al.,
1998; Sera and Wolffe, 1998). Thus, this oocytespecific transcriptional mechanism does not rely on
oocyte-specific factors. Rather, differential regulation
of shared or common factors results in this oocytespecific activity.
Oct-4: one of the early master gene regulators?
One of the few transcription factors known to be involved in the self-renewal of embryonic stem (ES) cells
is Oct-4. This factor belongs to the Pit-Oct-Unc (POU)
family of transcription factors containing both a
homeobox sequence and a POU-specific domain
(Verrijzer et al., 1992). It binds to an octamer motif
and interacts with DNA through a helix–turn–helix domain. Orthologs of Oct-4 in mice, bovines, and humans
share highly conserved genomic organization and regulatory regions (Nordhoﬀ et al., 2001; Kurosaka et al.,
2004).
Oct-4 is selectively expressed in totipotent embryonic
and germ cells (Pesce et al., 1998b; Pesce and Scholer,
2000). At the blastocyst stage in mammals, the outer
layer of the blastocyst is the trophectoderm and the cells
inside are the inner cell mass (ICM). The ICM is composed of pluripotent stem cells that give rise to all cell
types of the embryo, including the germ cell lineage.
Oct-4 mRNA is present uniformly throughout the morula stage and becomes restricted to the ICM of the
blastocyst (Fig. 5A). After embryo implantation in the
mouse, Oct-4 transcription is restricted to the epiblast
and ES cells (Yeom et al., 1996; Pesce et al., 1998a).
Oct-4 transcription is then progressively down-regulated during gastrulation and eventually conﬁned to the
PGCs (reviewed in Pesce and Scholer, 2000). This function is presumably involved in retention of germline
stem cell fates.
The candidate target genes that are up-regulated by
Oct-4 during mouse implantation include Fibroblast
Growth Factor-4 (FGF-4) and Osteopontin (OPN) (Guo
et al., 2002). FGF-4 is thought to stimulate ICM growth
or maintenance and is involved in the establishment of
the primitive endoderm in vivo (Wilder et al., 1997), and
OPN is an endodermal-specific, extracellular phosphoprotein that mediates adhesion by interacting with integrins (Guo et al., 2002). In contrast, both a and b
forms of human chorionic gonadotropin are downregulated by Oct-4 (Liu et al., 1997). Chorionic
gonadotropin prevents the regression of the corpus
luteum during early pregnancy, and is expressed by
trophectodermal cells. Therefore, Oct-4 functions as
both a transcriptional activator and repressor of its
different target genes in ensuring the end result of potency in ES cells.
Given its critical role in maintaining pluripotency of
the germ cells, Oct-4 is of special interest in our understanding of the continuity of the germline. The Oct-4
gene is driven by a TATA-less minimal promoter and at
least two enhancer elements (Okazawa et al., 1991;
Yeom et al., 1996). The minimal promoter contains a
GC box with putative-binding sites for Sp1 and Sp3
transcription factors and a hormone-responsive element
(HRE) (Sylvester and Scholer, 1994). The HRE contains binding sites for the steroid–thyroid receptor family and orphan nuclear receptor superfamily, specifically
COUP-TFI, ARP-1, EAR-2, and GCNF, which downregulate Oct-4 transcription (Okazawa et al., 1991;
Pikarsky et al., 1994; Sylvester and Scholer, 1994;
Ben-Shushan et al., 1995; Schoorlemmer et al., 1995;
Fuhrmann et al., 2001). The distal enhancer is necessary
for Oct-4 transcription in the morula, ICM, and PGCs,
while the proximal enhancer (PE) activates Oct-4 in the
epiblast (Yeom et al., 1996). The PE element is not only
a transcriptional enhancer but is also a cis-demodiﬁcation element that demethylates Oct-4 during specific
stages of embryogenesis, spermatogenesis, and oogenesis, when other genes undergo de novo methylation
(Ben-Shushan et al., 1993; Gidekel and Bergman, 2002;
Pan et al., 2002).
During gonadal development, transcription of Oct-4
in mouse and human germ cells remains high until the
onset of meiosis (Pesce and Scholer, 2000; Kurosaka
et al., 2004; Rajpert-De Meyts et al., 2004). Oct-4 transcription in oogonia and spermatogonia is down-regulated at specific stages of oogenesis and spermatogenesis
(Pesce et al., 1998a; Kurosaka et al., 2004; Rajpert-De
Meyts et al., 2004). In the spermatocyte lineage of the
adult mouse, Oct-4 protein is expressed in undifferentiated
A spermatogonia and is down-regulated as the germ
cells begin spermatogenic maturation (Pesce et al.,
1998a). Oct-4 expression in human testes is similar to
ﬁndings in mice, except that Oct-4 protein is undetectable from adult spermatogonia (Rajpert-De Meyts
et al., 2004). In mouse oocytes, Oct-4 mRNA and
8
Oct-4 upregulation
A
Zygote
4-cell
Cleavage
8-cell
Compacted
morula
Epiblast
ICM
B
12.5
13.5
14.5
15.5
16.5
17.5
18.5
1 dpp
2 dpp
3 dpp
Oct-4
expression
proliferation
arrest at diplotene
meiotic
entry
zygotene/pachytene
birth
Fig. 5 (A) Oct-4 expression in preimplantation and early postimplantation development in mouse. Present as a maternal transcript
in the zygote, Oct-4 is expressed at low levels until the eight-cell
stage, when the zygotic Oct-4 gene is turned on. Until the compaction of the morula, Oct-4 is expressed equally in all blastomeres
to be eventually conﬁned in the inner cell mass, and after implantation, in the epiblast. From Pesce et al. (1998a). (B) In female germ
cells, Oct-4 expression is down-regulated coincident with the entry
into the prophase of the ﬁrst meiotic division. At 15.5 dpc, correspondent to the zygotene/pachytene stage of meiotic prophase I,
Oct-4 is absent in oocytes. It is not re-expressed until birth, when
diplotene-arrested oocytes start expressing it de novo. Modiﬁed
from Pesce et al. (1998a).
protein are down-regulated when the oocyte enters prophase of the ﬁrst meiotic division and are re-expressed
near oocyte maturation (Fig. 5B) (Pesce et al., 1998a,
1998b). Similarly, in fetal human ovaries, Oct-4 is
present in primordial oogonia during fetal development
and is down-regulated in oocytes that entered the ﬁrst
meiotic prophase; some Oct-4 molecules might be transported to the cytoplasm at the onsest of meiosis, but the
biological significance of this phenomenon is unknown
(Rajpert-De Meyts et al., 2004). Oct-4 may play a role
in the growth or acquisition of meiotic competence of
oocytes, and/or it may be involved in transcriptional
repression of oocyte-specific genes, since Oct-4 is transcribed minimally during a time when the oocyte is
undergoing an overall increase in transcriptional activity, and Oct-4 is transcribed abundantly at oocyte maturation when transcriptional activity in the oocyte
decreases dramatically (Pesce et al., 1998b). Recently,
the expression of Oct-4 has been examined in human
testes and ovaries during fetal development, and its
aberrant expression may contribute to disorders in
sex differentiation and malignant gonadal tumors in
humans, highlighting its critical role in gonadal
development (Looijenga et al., 2003; Rajpert-De Meyts
et al., 2004).
The germ cell-specific transcription factor FIGa
regulates oocyte-specific genes
FIGa is a germ cell-specific transcription factor that
regulates the coordinated transcription of the three ZP
glycoproteins, ZP1, ZP2, and ZP3, and may regulate
additional pathways critical for ovarian development
(Fig. 6) (Liang et al., 1997; Dean, 2002). The ZP proteins form an extracellular matrix that surrounds the
growing mammalian oocyte and are critical for sperm
activation and for the block to polyspermy. Mouse ZP3
has been shown to contain the primary species-specific
sperm receptor of the oocyte, binding sperm via
O-linked oligosaccharide chains and inducing the sperm
9
Fig. 6 Model summarizing the expression and exchange of ALF
and TFIIA during oogenesis in Xenopus laevis. The model suggests
the exclusive use of the germ and somatic transcription factors ALF
and TFIIA in germline and somatic tissues. An earlier transition
from TFIIA to ALF is predicted at or about the time cells commit
to meiosis. The model also illustrates a transition from ALF to
TFIIA that occurs during maturation, fertilization, and early embryogenesis up to the mid-blastula transition (MBT). Modiﬁed
from Han et al. (2003).
acrosome reaction (Bleil and Wassarman, 1990; Cheng
et al., 1994, 1998; reviewed in Wassarman, 1988; Dean,
2002, 2004; Wassarman et al., 2004). Mouse ZP2 acts as
a secondary sperm receptor and plays a role in the prevention of polyspermy, while ZP1 cross-links the other
two ZP proteins (Wassarman et al., 2004). Targeted
mutagenesis in mice demonstrated that either ZP2 or
ZP3 homozygous nulls result in infertility in females but
not in males (Rankin et al., 2001). Mice lacking ZP1
have abnormal zona matrices that are more porous than
normal and result in early embryonic loss (Rankin
et al., 1999). In most vertebrates analyzed, including
mammals, Xenopus, and several ﬁsh, ZP genes are
present, active, and contribute to the egg’s extracellular
matrix, even though the extracellular matrix may vary
structurally. The transcription of ZP glycoproteins is
temporally and spatially restricted to oocytes in most
vertebrates (Wassarman, 1990; Epifano et al., 1995;
Kubo et al., 1997; Wang and Gong, 1999; Zeng and
Gong, 2002). However, in some organisms the ZP proteins are synthesized elsewhere. For example, the chick
ZP3 is synthesized by follicle cells surrounding the embryo and the ZP1 homolog is transcribed in the liver
(Waclawek et al., 1998; Bausek et al., 2000). In some
teleost ﬁsh species also, ZP components are transcribed
in the liver (Del Giacco et al., 1998).
Transcription of ZP genes in some organisms provides a paradigm for examining mechanisms and evolution of oocyte-specific gene transcription. In the
mouse, transcription of ZP proteins is coordinately regulated by FIGa (Liang et al., 1997). FIGa heterodimerizes with a ubiquitous b-helix–loop–helix
(bHLH) E12 protein and regulates the mouse ZP genes
by binding to a canonical E-Box (CANNTG) approximately 200 bp upstream of the transcription start sites
of ZP genes (Millar et al., 1991; Epifano et al., 1995;
Liang et al., 1997). Functional homologs of FIGa have
been identiﬁed in humans, zebraﬁsh, and medaka
(Liang et al., 1997; Kanamori, 2000; Huntriss et al.,
2002; Onichtchouk et al., 2003; Bayne et al., 2004), and
FIGa homologs bind interchangeably to the zebraﬁsh
ZPC and human ZP2 promoters, respectively (Onichtchouk et al., 2003; Bayne et al., 2004). FIGa is expressed in both the testis and ovary, but is expressed
most abundantly in the ovary of mouse (Liang et al.,
1997). FIGa is ﬁrst detected in oocytes at E13.5 in mice
and its transcript persists in oocytes into adulthood
(Liang et al., 1997). Mice lacking FIGa are unable to
express ZP genes or form primordial follicles, resulting
in massive depletion of oocytes and sterility (Liang
et al., 1997). However, cotransfection of FIGa and E12
in 10T1/2 embryonic ﬁbroblasts is not sufﬁcient to activate endogenous zona gene transcription, indicating
that FIGa plays an important regulatory role in conjunction with other, yet unknown factors (Liang et al.,
1997). Recently, the human FIGa homolog has also
been found to heterodimerize with E12 protein and bind
to the E-Box of the human ZP2 promoter, suggesting a
conserved mechanism in controlling ZP genes and primordial follicle formation in the human as in the mice
ovary (Bayne et al., 2004).
NoBox regulates oocyte-specific gene
transcription
The homeobox gene, Nobox (newborn ovary homeobox-encoding gene), was ﬁrst identiﬁed by in silico subtraction of a murine newborn ovary cDNA library
10
against the entire collection of mouse expression sequence tags (Suzumori et al., 2002). Nobox transcripts
are detected in both mouse male and female gonads by
reverse transcription-polymerase chain reaction (RTPCR), and in situ hybridization results indicated that
Nobox transcripts are present in murine oocytes from
primordial through antral follicles but not in somatically derived granulosa cells, theca cells, and corpora
lutea (Suzumori et al., 2002). NoBox protein localizes to
the nuclei of germ cells and primordial follicles in the
mouse ovary (Rajkovic et al., 2004). Disruption of 90%
of the Nobox coding region including the homeodomain
in the mouse resulted in infertile female mice, while
males were unaffected (Rajkovic et al., 2004). Histomorphometric analyses indicated that the relative numbers of oocytes, germ cells, and primordial follicles were
similar in Nobox1/ and Nobox / newborn ovaries (Rajkovic et al., 2004). However, by day 14 the
Nobox / ovaries revealed a great loss of oocytes,
indicating that the majority of oocyte and follicle
growth beyond the primordial follicle stage was disrupted by the absence of Nobox (Rajkovic et al., 2004).
Further examination indicated that in Nobox / ovaries, transcripts of genes that are preferentially transcribed in the oocyte, including Mos, Oct-4, Rfpl4, Fgf8,
Zar1, Dnmtlo, Gdf9, Bmp15, and H1oo, were downregulated (Rajkovic et al., 2004). The transcription of
Nobox precedes the transcription of these genes,
suggesting that Nobox may directly or indirectly regulate these genes that are important for oocyte and
early embryo development (Rajkovic et al., 2004). A
portion of the human Nobox homolog was also identiﬁed, but its function has not been examined (Suzumori
et al., 2002).
Germ cell-specific general transcription
factor ALF
The differentiation and restoration of totipotency of
germ cells involve tightly controlled gene expression
patterns. A set of general transcription factors are necessary for an accurate initiation of transcription. ALF
(TFIIAt) is a counterpart of the large a/b subunit of the
general transcription factor TFIIA. ALF interacts with
the small TFIIA subunit to form a heterodimeric complex that stabilizes binding of TBP (TATA-binding
protein) to core promoter DNA. ALF is transcribed
specifically in testis and ovary of Xenopus and mice
(Han et al., 2001). It was ﬁrst identiﬁed in male germ
cells and is expressed during the pachytene stage of
meiotic prophase I in males (Han et al., 2001). In immature Xenopus oocytes, the maternal TFIIAa/b
mRNAs are translationally repressed through a conserved 3 0 UTR, and ALF compensates for the maternal
storage and inactivation of TFIIa/b mRNAs (Han
Fig. 7 Multiple targets for FIGa. FIGa heterodimerizes with a
ubiquitous bHLH protein, E12, and binds upstream of one or more
genes, the expression of which is required for primordial follicle
formation. In addition, FIGa is required for the expression of the
three zona pellucida genes (Zp1, Zp2, and Zp3), without which the
zona matrix is not formed. The persistence of FIGa in oocytes from
embryonic day 13 until the oocytes are fully grown suggests that
FIGa may regulate additional genes that are important for normal
oogenesis and early development. From Soyal et al. (2000).
et al., 2003). When oocytes commit to meiosis, a transition from TFIIAa/b to ALF occurs, and during maturation, fertilization, and early embryogenesis, ALF is
inactivated and replaced by somatic TFIIAa/b (Fig. 7)
(Han et al., 2003).
The transcriptional regulation of ALF in male germ
cells is associated with reduced methylation at promoter-proximal CpG dinucleotides, whereas silencing
in somatic tissues is associated with increased methylation (Xie et al., 2002). The promoters of mouse and
human ALFs contain a short GC-rich region that is
active when transfected into COS-7 and 293 cells (Xie
et al., 2002). Transgenic mice containing this 133 bp
ALF promoter linked to b-galactocidase and GFP reporter genes indicated that this promoter fragment was
sufﬁcient to direct specific transcription of ALF in both
male and female germ cells (Han et al., 2004). Factors
that regulate the differentiated transcription of ALF,
however, have not been identiﬁed. The results from
Xenopus and mice suggest an evolutionary conserved
role for ALF in the germ cell differentiation programs.
ALF is one of a few germ cell-specific general transcription factors identiﬁed to date. Similar critical
regulators of the gene transcription program directing
male gametogenesis in the fruit ﬂy are the Drosohpila
testis-specific TAF homologs: the cannonball (homolog
of dTAF5), nht (homolog of dTAF4), mia (homolog of
dTAF6), sa (homolog of dTAF8), and rye (homolog
of dTAF12) (Lin et al., 1996; Hiller et al., 2001, 2004).
Mutations in can, nht, sa, and mia all block spermatid
differentiaion. ALF may regulate germ cell-specific gene
expressions during gametogenesis, since RNA polymerase II does not initiate transcription efﬁciently
without general transcription factors, including TFIIA.
Examination of the transcriptional regulation of
ALF indicates that epigenetic modiﬁcation such as
11
methylation may be an important regulatory mechanism of transcription. Identiﬁcation of germ cell-specific
transcription factor ALF and other tissue-specific
TAF homologs suggest that the germ cell genome has
evolved specialized transcription machinery to ensure
the proper activation of genes that are required for germ
cell development.
that leads to oocyte atresia (Schmidt et al., 2004).
Therefore, proper gene expressions in ovarian somatic
cells, as exempliﬁed by TAFII105 and FOXL2, affect
the growing oocyte and contribute to the proper overall
ovarian development.
Potential oocyte-specific regulatory factor—
Oogenesin
Tissue-specific transcription factors important
for somatic contribution to oogenesis
Ovarian development involves combinatorial factors
present in both the oocytes as well as in the somatic
ovarian tissues. Transcription factors expressed by the
follicular cells in the ovarian tissue are also now known
to be important for oogenesis, such as the mouse
TAFII105 and FOXL2 factors. TAFII consists of TBPassociated factors that are part of the TFIID general
transcription initiation complex. The TFIID complex
binds to the core promoters and directs RNA polymerase II to begin transcription. TAFII105 is highly expressed in granulosa cells that surround the maturing
mouse oocytes and in the testis (Freiman et al., 2001).
Female mice lacking TAFII105 are viable but are sterile,
whereas male mice lacking TAFII105 are both viable
and fertile (Freiman et al., 2001). TAFII105 controls
gene transcription during female gametogenesis as a
tissue-specific TFIID subunit. Microarray analysis of
heterozygous and knock-out TAFII105 ovaries indicated down-regulation of ovarian-specific genes, including
inhibin, aromatase, follistatin, cyclin D2, and 17-bhydroxysteroid dehydrogenase type I (Freiman et al.,
2001). These ﬁndings suggest that tissue-specific
TFIID-related factors are important in the developmental regulation of gene transcription in gonadal development.
Another transcription factor important for ovarian
development and function is FOXL2, a winged helix/
forkhead transcription factor that is highly conserved in
sequence and pattern of transcription in the early development of the vertebrate female gonad (Cocquet
et al., 2003). Mutations in FOXL2 cause the blepharophimosis–ptosis–epicanthus
inversus
syndrome
(BPES), characterized by eyelid malformations and
premature ovarian failure in humans (Cocquet et al.,
2002, 2003). FOXL2 is expressed in mammalian ovaries
early in development, even before the onset of folliculogenesis, and persists until adulthood (Cocquet
et al., 2003). The FOXL2 mRNA is detected in both
granulosa cells and some oocytes of the fetal and
adult mouse ovaries (Loﬄer et al., 2003), although the
FOXL2 protein is present only in follicular granulosa
cells (Cocquet et al., 2002; Schmidt et al., 2004). Female
mice lacking FOXL2 have a depleted pool of primordial
follicles because of granulosa cell differentiation failure
Most of the known gonadal transcription factors are
present in both the testis and ovary, or the so-called
‘‘germline-specific’’ factors. These include FIGa, NoBox, and ALF transcription factors. Recently, two
groups have independently identiﬁed an oocyte-specific
superfamily of leucine-rich proteins, oogenesin-1–4, by
two different methods. Dade et al. (2003) used in silico
subtraction of cDNA libraries generated from mouse
unfertilized eggs and two-cell zygote to identify oogenesin-1–4. Using differential display comparing RNA
transcription of mouse oocytes and preimplantation
embryos, Minami et al. (2003) identiﬁed oogenesin-1,
which is transcribed in ovaries from 15.5 dpc fetus,
coinciding with the start of oogenesis. Oogenesin-1
mRNA and protein are localized in oocytes in primordial, primary, secondary, and antral follicles in the
mouse ovary, but in contrast, oogenesin-2–4 mRNAs
are detected in oocytes from primary to preovulatory
follicles but are not detectable in the primordial follicles
(Dade et al., 2003). Low levels of oogenesin-4 transcripts are detected, however, in the testis. The exact
roles of oogenesin proteins are not known. Since oogenesin-1 is expressed in the oocytes coincident with the
start of primordial follicle formation, oogenesin-1 may
be involved in oocyte–somatic cell interactions that lead
to folliculogenesis (Minami et al., 2003).
Potential regulatory role of Sox in ovarian
development
The Sox proteins belong to the SRY-type HMG (high
mobility group) box superfamily of DNA-binding proteins. They are involved in the regulation of diverse
developmental processes such as germ layer formation,
organ development, sex determination, and cell type
speciﬁcation and are found in all metazoan species (reviewed in Wegner, 1999; Wilson and Koopman, 2002).
Sox3 is homologous to the SRY gene (Sex-determining
Region of the Y chromosome) and is expressed in the
mouse brain and both gonads of the mouse (Collignon
et al., 1996; Weiss et al., 2003). In the mouse, Sox3 was
determined to be required for gonadal function but not
in sex determination in both males and females (Weiss
et al., 2003). The mouse Sox3 protein was localized in
Sertoli cells of the testis and not in the ovary, although
12
transcripts of mouse Sox3 are detected in oocytes and
cumulus cells in the ovary (Weiss et al., 2003). The Sox3
knock-out mice exhibited abnormal growth, tooth development, and altered function of the somatic and
germ cells in both sexes (Weiss et al., 2003). Therefore,
Sox3 may play a role in gonadal development; however,
its target genes have yet to be identiﬁed.
Other transcription factors expressed in
the gonads
An increasing number of transcription factors are found
to be expressed in the gonads, but their roles in gonadal
development are not known. Northern blot analyses
and RT-PCR from adult mouse tissues identiﬁed six
Obox (oocyte-specific homeobox) family transcripts
that are preferentially expressed in the gonads and that
are distinct from the NoBox transcription factors (Rajkovic et al., 2002; Yeh et al., 2002). Obox-1, 2, 3, and 6
mRNA were detected in oocytes, and Obox-4 transcripts were detected in the testes (Rajkovic et al., 2002;
Yeh et al., 2002). The protein localization of Obox has
not been determined, but they may function either in
transcriptional activation of the oocyte genome within
the growing follicle, and/or they may be maternal factors that play a role in early embryogenesis.
Several groups have examined the transcription and
function of homeotic genes in mouse, human, and bovine oocytes and preimplantation stage embyros
(Verlinsky et al., 1995; Kuliev et al., 1996; Adjaye and
Monk, 2000; Ponsuksili et al., 2001; Villaescusa et al.,
2004). In vertebrates, HOX homeobox-containing genes
are arranged on four separate chromosomal clusters, A,
B, C, and D (reviewed in Gehring et al., 1994). Previous
studies using RT-PCR detected HOXA4, HOXA7, HOXB4, HOXB5, HOXD8, and HOXD1 in human oocytes
and cleaving embryos (Verlinsky et al., 1995; Kuliev
et al., 1996). In addition, the ubiquitously expressed
POU family member Oct1, and HEX (Homeotic gene
Expressed in the Hematopoiesis) were detected in cDNA
libraries derived from human unfertilized oocytes and
early embryos (Adjaye and Monk, 2000). In bovine
oocytes, HOXA3 and HOXD1 mRNA were detected,
with HOXD1 also present in the four-cell stage bovine
embryo (Ponsuksili et al., 2001). A similar study was
conducted to identify HOX genes expressed in the
mouse ovary resulting in the identiﬁcation of HOXA5,
HOXA9, HOXB6, HOXB7, HOXC6, and HOXC8 and
HOX co-factors PREP and PBX (Villaescusa et al.,
2004). The role of HOX transcription factors in mammalian oocytes and early embryonic stages remains to
be elucidated.
Summary
The diverse families of transcription factors discussed
in this review include regulatory proteins that are
expressed predominantly in oocytes, proteins that are
enriched in the gonads, and proteins that are present
in oocytes, gonads, and early embryos (Table 1). A
survey of existing studies on transcription factors that
Table 1 Summary of transcription factors involved in gonadal development
RNA expression
Protein localization
Oocytes
Sperm
Somatic
ovary
Somatic
testis
Oocytes
Sperm
Somatic
ovary
Somatic
testis
Oct-4
111
111
111
111
FIGa
111
N/D
11
111
N/D
N/D
NoBox
111
N/D
1
111
N/D
N/D
ALF
TAFII105
FOXL2
111
1
111
N/D
1
111
111
1
1
111
N/D
111
N/D
N/D
N/D
111
N/D
N/D
Oogenesin-1–3
111
1112
N/D
2
N/D
Oogenesin-4
mSox3
Obox 1, 2, 3, 6
111
1
11
N/D
11
11
11
N/D
N/D
N/D
N/D
N/D
N/D
N/D
1
N/D
Obox 4
N/D
11
N/D
N/D
N/D
N/D
1
Not distinguished between sperm and somatic testis.
Oogenesin 1 only.
, not detected; N/D, not determined.
2
Kurosaka et al. (2004),
Pesce et al. (1998a, 1998b)
Liang et al. (1997),
Soyal et al. (2000)
Rajkovic et al. (2004),
Suzumori et al. (2002)
Han et al. (2003, 2004)
Freiman et al. (2001)
Cocquet et al. (2002, 2003),
Loﬄer et al. (2003),
Schmidt et al. (2004)
Dade et al. (2003),
Minami et al. (2003)
Dade et al. (2003)
Weiss et al. (2003)
Rajkovic et al. (2002),
Yeh et al. (2002)
Rajkovic et al. (2002)
13
4
Oct-
gonadal ridge: PGCs develop into oogonia
GDF-9
BMP-15
TF 1, 2, 3
e.g. vasa
nanos
germ-cell-less
-4
Oct
oogonial proliferation
early embryo: PGC specification
input signals
TF A, B, C
oogonia transition
to primary oocytes
input signals
Figα
Nobox
oocyte growth and development
target genes for differentiation
YP30
ZP1, 2, 3
SFE 1, 9, Opo, Pln, Rdv
mature egg
Fig. 8 Model of a putative transcriptional network during the life
cycle of oocytes. The process begins with the formation of primordial germs cells, followed by oogonial stem-cell proliferation, entry
into meiosis, and oocyte differentiation. Shown are several factors
involved in PGC formation (vasa, nanos, germ cell less), in stemcell propagation (Oct-4), in somatic–germ cell interaction (GDF-9,
BMP-15) and in oocyte development (FIGa, Nobox). Known
oocyte-specific differentiation products are also shown: YP30,
ZP1–3, and the cortical granule contents SFE1, 9, ovoperoxidase,
proteoliaisin, and rendivin. TF1–3 represent putative pre-meiotic
transcription factors that promote mitotic proliferation and inhibit
germ cell differentiation. TF A, B, and C are putative post-meitoic
transcription factors that promote meiosis, egg maturation, and
differentiation. Arrows indicate positive interactions, and bars indicate a repressive function.
have a putative role in gonadal development revealed
that the majority of regulatory proteins are not restricted to oocytes, but rather, are present elsewhere in
the animal. Therefore, the majority of transcriptional
mechanisms used in the oocyte will likely center on differences in the regulation of populations of transcription factors that overlap somatic cells of the gonad,
embryo, or adult. Studies on gene regulation of 5S
RNA, Oct-4, and ALF suggest that chromatin remodeling events such as histone acetylation and DNA methylation are at least part of the molecular mechanism
that regulates transcription of these genes. It is likely
that the interaction between the chromatin structure
and transcription factors together determine the transcriptional activity of specific sets of genes during
gametogenesis. The transcriptional regulatory machinery in specifying oocyte development may involve a
unique combination of only a few master transcription
factors, such as FIGa in regulating oocyte-specific
ZP genes in the mouse, utilization of tissue-specific
general transcription machinery, interactions with chromatin remodeling and modiﬁcation complexes, and
hormonal signals.
Concluding remarks and future perspectives
Oocytes go through many transitions in their life history. These begin with the speciﬁcation of the PGCs in
the embryo, the entry of the germ cells into the gonadal
rudiment, the transition of oogonial stem cell to a primary oocyte, and their development into a mature, fertilizable egg. These developmental stages must entail a
dynamic network of gene expressions. One model to
explain these changes is that this single cell undergoes
progressive transitions in transcription factor proﬁles
and activities (Fig. 8). While currently we are in a phase
of identifying what factors might be present, with dramatic new knowledge in genomics even in oocyte biology, we will quickly confront the problem of how the
accumulated factors identiﬁed in oocytes interact to
propel the cell forward in a developmental scheme. One
would invoke a network of interacting trans-factors
with the cis-regulatory elements of the promoters of
select transcription factors to regulate the specific expression of these factors. Once a certain level of such a
target factor has been achieved, feedback—either directly, or indirectly through additional transcription
factors—would up- or down-regulate transcription of
the ﬁrst factor.
In addition, because of the prolonged periods required for oocyte development, homeostasis of transcription-stable periods would require feedback in the
form of a network of positive and negative interactions.
While some of these processes are shared with other
cells, understanding the oocyte transcriptome would be
of great utility to our understanding of germ cells specifically, or stem cells in general. Thus, for both changes
in oocyte development and for homeostasis, feedback
regulation in the transcriptional proﬁle of oocytes is a
necessary process that needs further attention.
Acknowledgments
We thank Dr. Richard Freiman for his critical
reading of this review. We thank Judith Nathanson for ﬁgure construction. This work is supported by grants from the NIH and NSF.
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