Download Mouse genetics provides insight into folliculogenesis, fertilization

Human Reproduction Update, Vol.8, No.5 pp. 395±403, 2002
Mouse genetics provides insight into folliculogenesis,
fertilization and early embryonic development
Asma Amleh1 and Jurrien Dean
Laboratory of Cellular and Developmental Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
1
To whom correspondence should be addressed at: Laboratory of Cellular and Developmental Biology, NIDDK, Room 3133,
Building 50, National Institutes of Health, Bethesda, Maryland, 20892-8028. E-mail: [email protected]
After colonization of the gonad, mouse female germ cells enter into the prophase of the ®rst meiotic division as a
mid-gestational hallmark of gender. Perinatally, oocytes interact with granulosa cells to form primordial follicles
which, with cyclic periodicity, enter into a 3-week growth phase that culminates in meiotic maturation and ovulation.
Successful fertilization in the oviduct results in the onset of embryogenesis. Genes expressed in oocytes encode
maternal factors that control many of these developmental processes. The establishment of mouse models in which
speci®c genes have been disrupted offers robust insights into molecular mechanisms that control oogenesis,
folliculogenesis, fertilization and early embryogenesis. Although relatively few developmental circuits have been
characterized in genetic detail, the ongoing revolution in mouse genetics holds great promise. These model systems
provide novel information into the molecular basis of the pathways required for oocyte-speci®c processes as well as
for interactions with the temporally changing environment of female germ cells. The similarities between the mouse
and human genomes provide assurance that this knowledge will rapidly translate into a better understanding of
human reproduction.
Key words: folliculogenesis/maternal factors/meiotic maturation/oogenesis/transgenesis
TABLE OF CONTENTS
Introduction
Origin of female germ cells
Oocyte-speci®c factors affecting folliculogenesis
Oocyte maturation
Fertilization
Early embryogenesis
Summary
Acknowledgements
References
Introduction
During folliculogenesis, oocytes grow as the surrounding
granulosa cells proliferate and differentiate. The subsequent
maturation of the oocyte and completion of the ®rst meiotic
division occurs as the oocyte is ovulated into the oviduct in
preparation for fertilization. Unlike the male gonad in which
seminiferous tubules are formed in the absence of germ cells,
folliculogenesis does not occur in the absence of oocytes. This
suggests that there are interactions between the germ and
granulosa cell compartments that are critical for successful
growth of a follicle. During oogenesis, there is accumulation of
maternal proteins that are of importance not only for successful
Ó European Society of Human Reproduction and Embryology
folliculogenesis and germ cell maturation, but also for the
activation of the embryonic genome and early development.
Rather than a broad survey of this substantial ®eld, this review
will focus on recent examples of genes critical for oocyte success,
the functions of which have been elucidated by molecular biology
and mouse genetics.
Origin of female germ cells
Mammalian germ cell lineage is established early during fetal
development. In the mouse, primordial germ cells (PGC) are ®rst
detected ~7.25 days after fertilization (embryonic day E7.25) as a
cluster of cells identi®ed by their high content of alkaline
phosphatase (Ginsburg et al., 1990). However, the germ cell
lineage arises earlier and has been traced to the proximal region of
the epiblast close to the extra-embryonic ectoderm (Lawson and
Hage, 1994). A subset of these cells is swept into the extraembryonic mesoderm where, under the in¯uence of non cellautonomous factors, such as bone morphogenetic protein 4
(BMP4), they differentiate into PGC (Fujiwara et al., 2001).
Bmp4 homozygous null mutants fail to generate PGC, and the
heterozygous mutant mice have reduced number of PGC (50%
that of the wild type), suggesting that the activity of BMP4 is dose
dependent. Another member of the BMP superfamily (BMP8B)
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also appears to be required for PGC generation (Ying et al., 2000)
and there is evidence that BMP4 and BMP8B signalling pathways
act synergistically (Ying et al., 2001). Smad 1 and 5 (vertebrate
homologues of C. elegans SMA and D. melanogaster MAD
proteins) are thought to act downstream of the BMP signalling
pathway and their loss results in decreased numbers of primordial
germ cells (Massague and Chen, 2000; Chang and Matzuk, 2001;
Tremblay et al., 2001).
Oct4 expression faithfully follows the germ cell lineage. Oct4
transcripts are ®rst detected in the epiblast during gastrulation
(~E6.5) and later became restricted to PCG located in the extraembryonic mesoderm (Yeom et al., 1996). The germ cells
subsequently enter the embryo proper and migrate to the
urogenital ridge ~E10. Migration of PCG through the hind gut
along the mesentery towards the future gonad is thought to be
mediated by a tyrosine kinase receptor (KIT) expressed on the
surface of PGC, and its ligand (KL/Steel/SCF), which is
expressed in the somatic cells along the migratory pathway
(Matsui et al., 1990; Keshet et al., 1991). Mutations in either the
KIT receptor or ligand result in female gonadal dysgenesis and
sterility (Mintz and Russell, 1957; McCoshen and McCullion,
1975). Female PGC in the gonad enter meiosis ~E13.5, an event
that is a hallmark of the ovarian development. Ovarian somatic
cell differentiation, unlike that of the testis, requires the presence
of oocytes (McLaren, 1991).
Atm (ataxia-telangiectasia-mutant) and Dazl1 (deleted-inazoospermia-like-1) are expressed in murine germ cells and are
essential for PGC survival/development. Atm encodes a nuclear
protein that has been implicated in double-stranded DNA break
repair and cell cycle control. In male and female ATM-de®cient
mice, gametogenesis is disrupted early in the leptotene stage of
meiosis and the mice are sterile (Barlow et al., 1998). Dazl1
encodes cytoplasmic protein with RNA binding motifs hypothesized to affect translation. Male and female mice lacking the
Dazl1 gene lose their germ cells prenatally (McNeilly et al., 2000)
and are sterile, although the mechanism of germ cell loss remains
to be determined.
Oocyte-speci®c factors affecting folliculogenesis
The female gamete grows and undergoes meiotic maturation
during folliculogenesis. This process begins in the latter stages of
fetal development when primordial germ cells enter meiosis and
arrest at the end of prophase (dictyate in mice). Many of the
molecules de®ning genetic circuits that control progression of
oogenesis remain unknown. In the fetal mouse ovary, germ cells
normally form clusters due to cell division with incomplete
cytokinesis (Ruby et al., 1969; Pepling and Spradling, 1998).
These germ-line syncytia undergo a developmentally programmed breakdown associated with invasion of pre-granulosa
cells just prior to primordial follicle formation (Pepling and
Spradling, 2001). In the neonatal ovary, each surviving dictyate
oocyte is enclosed in a layer of ¯attened pre-granulosa cells
which, in turn, are surrounded by a basal lamina to form
primordial follicles (Hirsh®eld, 1991).
The primordial follicles in the newborn mouse ovary represent
the entire complement of germ cells available for reproduction.
After birth, cohorts of primordial follicles are periodically
recruited to enter into a 3-week growth phase. Concomitant with
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the growth of oocytes, the granulosa cells transform to acquire a
cuboidal shape, forming primary follicles. The proliferation of
granulosa cells results in pre-antral follicles composed of
multilayers of granulosa cells surrounding the oocyte within the
follicular basement membrane. After puberty, further growth of
follicles is accelerated by gonadotrophins, FSH, leading to the
formation of antral follicles (Kumar et al., 1997). Although
oocytes within large antral follicles are competent for maturation,
they remain arrested due to their interaction with the surrounding
granulosa cells (Bornslaeger et al., 1986). In response to the LH
surge, fully grown oocytes complete the ®rst meiotic division,
extrude the ®rst polar body, and become arrested at metaphase II
(MII) (Richards et al., 2002).
The LH surge is responsible for ovulation of the oocyte
marking the end of folliculogenesis (Lee et al., 1996). The
number of follicles that ovulate compared to those that are
recruited for growth in any given cycle is smaller because the
majority of follicles undergo atresia (Richards, 1980; Hirsh®eld,
1989). Follicles may become atretic at any stage of development,
but mostly at the pre-antral and early antral stages. Death of the
oocyte within the follicle occurs either intrinsically or as a
consequence of follicular cell death. It remains to be determined
why the majority of oocytes undergo atresia and only a few
proceed to ovulation.
Folliculogenesis and oogenesis are coupled processes that are
co-ordinated through gap junction communication resulting in
mature oocytes competent for fertilization and embryonic
development. No follicle is formed without an oocyte and oocyte
development is regulated by the surrounding granulosa cells. The
oocyte secretes signals that induce follicle formation, prompt
granulosa cell proliferation, regulate steroidogenesis, and maintain the architecture of the developing follicle. Similarly, signals
from granulosa cells regulate meiotic arrest, promote oocyte
growth and facilitate the resumption of meiosis and oocyte
maturation (Eppig, 2001; Epifano and Dean, 2002). Determining
the roles of genes expressed in the oocyte should provide insight
into critical events involved in the ovarian development. The few
genes that have been identi®ed as exclusively expressed in the
oocyte appear to function as multipurpose factors throughout
folliculogenesis and/or early embryogenesis (Figure 1).
Factor In the Germline, alpha
Factor In the Germline, alpha (FIGa), a germ-cell speci®c basic
helix±loop±helix (bHLH) transcription factor, has been implicated in the coordinate expression of the three zona pellucida
genes (Zp1, Zp2, Zp3) (Liang et al., 1997). In addition, female,
but not male, mice that are de®cient in FIGa are infertile (Soyal et
al., 2000). No primordial follicles are formed in the ovaries of the
newborn Figa null females despite normal embryonic gonadogenesis and oogenesis. It has been demonstrated that comparable
numbers of null and normal oocytes reach the pachytene and
diplotene stages of meiotic prophase. However, within the ®rst
week after birth, ovaries of the Figa null females are devoid of
oocytes. Whether FIGa is involved in oocyte survival or in
regulating the initial granulosa±oocyte interactions remains to be
determined. As expected, ZP1, ZP2 and ZP3 transcripts are not
detected in ovaries of the Figa null females when examined prior
to oocyte depletion. These results indicate that FIGa plays a key
regulatory role in the expression of at least two oocyte-speci®c
Mouse models for human reproduction
Figure 1. Genes implicated in folliculogenesis. Perinatally, FIGa, a basic helix±loop±helix transcription factor, is required for the formation of the primordial
follicle. Progression to the secondary stage of folliculogenesis requires germ-cell speci®c growth factors including GDF9 and BMP15. Oocytes lacking
CONNEXIN37 are unable to form effective gap junctions between germ and granulosa cells and do not mature beyond the early antral stage of folliculogenesis.
The genes encoding these factors are indicated as Figa (Factor in the Germline, alpha), Gdf9 (Growth and Differentiation Factor 9), Bmp15 (Bone Morphogenetic
Factor 15) and Cx37 (Connexin 37).
pathways, those that initiate folliculogenesis and those that
express the three genes encoding the zona pellucida. The
persistence of FIGa transcripts in adult ovaries suggests that it
may regulate additional pathways. Furthermore, the presence of
FIGa transcripts (and, presumably protein) in fetal ovaries at E13
may in¯uence genes that regulate the earliest events of oogenesis.
Growth and differentiation factor 9
As oocytes enter the growth phase of oogenesis, they produce
GDF9, which promotes early granulosa cell proliferation and
induces differentiation of cumulus cells later at the antral stage of
folliculogenesis (Elvin et al., 1999b). GDF9 is a member of the
TGFb super family of secreted signalling proteins. In ovaries of
female mice that are de®cient in GDF9, follicles do not grow
beyond the primary stage, while oocytes grow in size, but
eventually degenerate within the primary follicle (Dong et al.,
1996). Interestingly, these granulosa cells are competent to
undergo luteinization while the fully-grown oocyte never acquires
the competence for maturation. Recombinant mouse GDF9
induces the expression of cyclooxygenase 2 (COX-2),
STeroidogenic Acute Regular protein (StAR), and increases
granulosa cell progesterone synthesis in the absence of FSH in
vitro (Carabatsos et al., 2000; Dong et al., 1996). Furthermore,
GDF9 promotes cumulus expansion in oocytectomized follicles
by inducing the hyaluronidase synthetase gene and by inhibiting
the expression of urokinase plasminogen activator (Elvin et al.,
1999a). Thus, it appears that GDF9 plays a critical role in the
successful growth and differentiation of follicles.
Bone morphogenetic protein 15
Bmp15, also known as Gdf9b, is an X-linked gene that is
expressed exclusively in oocytes, and its protein product has a
high degree of homology (52%) with GDF9. Similar to Gdf9,
Bmp15 gene expression is ®rst detected in oocytes within primary
follicles and its protein product stimulates granulosa cell
proliferation (Carabatsos et al., 1998; Dube et al., 1998; Otsuka
et al., 2000). In addition, BMP15 selectively inhibits FSHinduced progesterone production, but not FSH-induced estradiol
production, due in part to the regulation of FSH receptor
transcription (Otsuka et al., 2001). Female mice that are de®cient
in BMP15 are subfertile with reduced litter size due to ovulatory
defects (Yan et al., 2001). Furthermore, not all BMP15 de®cient
oocytes, when fertilized, are competent for preimplantation
embryonic development. By examining and characterizing mice
with Bmp15±/±, Gdf9+/± or Bmp15±/±, Gdf9±/± double mutants, it
has become clear that BMP15 and GDF9 proteins have synergistic
roles in ovarian function.
Unlike Bmp15±/± null female mice, sheep that are de®cient in
BMP15 are sterile due to an arrest in folliculogenesis and
phenocopy female mice de®cient in GDF9. Interestingly, sheep
heterozygous for a Bmp15 null allele display increased fertility
compared to normal, suggesting that fertility is regulated by
BMP15 in a dosage sensitive manner (Galloway et al., 2000).
Species-speci®c models have been proposed to incorporate these
disparate observations. In mice, GDF9 homodimers would be the
most bioactive based on the phenotype of mouse Gdf9±/± and
Bmp15±/± as well as the results of an in-vitro bioassay which
examined the activity of GDF9 and BMP15 homodimers. In
sheep, the data suggest that BMP15 homodimers are the most
bioactive compared to either GDF9 homodimers or BMP15/
GDF9 heterodimers (Yan et al., 2001).
Oocyte maturation
Meiotic maturation
The acquisition of meiotic maturation competence occurs in two
steps during oocyte growth. The germ cell ®rst gains the ability to
undergo germinal vesicle breakdown (GVBD) and progress to
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metaphase I (MI) (Canipari et al., 1984; Chesnel and Eppig,
1995), and then the ability to progress to MII (Sorensen and
Wassarman, 1976; Wickramasinghe et al., 1991). Resumption and
completion of meiosis in the oocyte involve orchestration of three
major factors: MPF (Maturation Promoting Factor), MOS (a
proto-oncogene), and MAPK (Mitogen Activated Protein Kinase).
MPF is a protein complex composed of a catalytic subunit,
p34cdc2, and a regulatory subunit, CYCLIN B (O'Keefe et al.,
1991). In mouse, MPF activity precedes GVBD and is believed to
initiate a cascade of events leading to protein phosphorylation,
which drives the oocyte through meiotic progression (Araki et al.,
1996; Choi et al., 1996). However, a transient decrease in MPF,
associated with attenuated CYCLIN B, is necessary for the
extrusion of the ®rst polar body. Thus, the rates of CYCLIN B
synthesis and degradation determine the timing of the major
events during mouse oocyte meiotic maturation (Ledan et al.,
2001). It appears that MPF requires the phosphatase action of
Cdc25b to become functionally active. Ovaries of female mice
lacking Cdc25b protein provide oocytes that fail to undergo
GVBD despite their passage through normal folliculogenesis
(Lincoln et al., 2002).
The proto-oncogene MOS, which is a member of the serine/
threonine protein kinase family, appears to be required for the
activation of MAPK. MOS mRNA in the growing oocyte is
transcriptionally dormant with short polyA tails (Paynton and
Bachvarova, 1994; Salles et al., 1992). Upon GVBD, the polyA
tail is elongated by polyadenylation and MOS mRNA becomes
translationally activated. Subsequently, MOS proteins appear to
be required for the activation of MAPK (Colledge et al., 1994;
Hashimoto et al., 1994). The MOS/MAPK pathway is responsible
for proper spindle formation at MI and MII, repression of DNA
replication at the MI-MII transition and maintenance of the MII
arrest (Verlhac et al., 1993; Colledge et al., 1994; Gebauer et al.,
1994; Hashimoto et al., 1994; Araki et al., 1996).
Gap junctions
During folliculogenesis, oocytes and the surrounding granulosa
cells extend cellular processes towards one another and establish
gap junctions by which the cells in the follicle communicate.
While these gap junctions maintain the communication between
the oocyte and granulosa cells implicated in meiotic arrest, there
is evidence that they also mediate activating events leading to
oocyte maturation (Eppig, 1991). Gap junctions are formed by
connexin proteins, some of which are ubiquitous and others which
have more restricted spatial and developmental patterns of
expression (White and Paul, 1999). CONNEXIN 37 (CX37) is
expressed by the oocyte at all stages of folliculogenesis and
participates in the formation of these gap junctions. In CX37de®cient female mice, follicle development fails at the pre-antral±
antral transition resulting in sterile females (Simon et al., 1997). It
has been shown that oocytes released from pre-antral follicles of
Cx37 null mice respond to a protein phosphatase inhibitor
(okadiac acid) and enter M phase of meiosis (Carabatsos et al.,
2000). However, Cx37 null oocytes are unable to maintain the M
phase after removal of okadiac acid, suggesting that acquisition of
oocyte cytoplasmic maturation is dependent on gap junction
formation, but that nuclear maturation is not. Mice with targeted
disruption of Cx43 (expressed in granulosa cells) are de®cient in
germ cells. Those that are present form follicles, but do not
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progress beyond the primary or early secondary stage. In the
absence of CX43, intercellular coupling between granulosa cells
is reduced, leading to an early arrest in folliculogenesis and severe
disruption of germ cells (Ackert et al., 2001).
Zona pellucida
An important component of growing follicles is the extracellular
zona pellucida that separates the oocyte from the surrounding
granulosa cells. The zona pellucida is synthesized in oocytes and
is ®rst detected in primary follicles as patches of coalesced
extracellular matrix. As oocytes grow, the zona pellucida
increases in width from 3 mm in the secondary follicle to 7 mm
in the early antral follicle (Dietl, 1989). The matrix is composed
of three sulphated glycoproteins, ZP1, ZP2, ZP3. ZP2 and ZP3 are
major, approximately equal components, and ZP1 represents 10±
15% of the zona mass (Bleil and Wassarman, 1980b). The role of
the individual zona proteins in the formation of the matrix has
been investigated using mouse lines with null mutations in each of
the single copy Zp1, Zp2 or Zp3 genes (Liu et al., 1996; Rankin et
al., 1999, 1996, 2001). Although normally the zona matrix is
composed of all three proteins (ZP1/ZP2/ZP3), a zona matrix can
be formed with either ZP1/ZP3 or ZP2/ZP3, suggesting that only
ZP3 is essential for zona pellucida formation. However, the ZP1/
ZP3 zona matrix is particularly thin and does not persist past the
formation of the antral stage of folliculogenesis. Oocytes lacking
ZP2 or ZP3 develop, but the latter stages of folliculogenesis are
perturbed and relatively few zona-free oocytes are recovered in
the oviduct after gonadotrophin-stimulated ovulation. While these
zona-free oocytes can be fertilized in vitro and progress to the
blastocyst stage, no live births have been observed after transfer
to pseudopregnant females. These results suggest that the
morphologic abnormalities observed during folliculogenesis in
the Zp2 and Zp3 null mutants adversely affect the developmental
competence of the zona-free oocytes after fertilization. Mice
lacking ZP1 have a fairly robust-looking zona matrix, but there is
ectopic localization of granulosa cells in the perivitelline space
between the oocyte's plasma membrane and the inner aspect of
the zona pellucida in ~10% of the growing follicles. ZP1 is the
only zona protein that forms inter-molecular disulphide bonds,
and may therefore provide structural integrity to the zona
pellucida beyond its relatively minor contribution to the mass of
the zona pellucida.
Fertilization
After ovulation, the zona pellucida mediates both the initial
sperm±oocyte recognition and triggers the acrosome reaction.
There is in-vitro evidence that the sperm recognizes ZP3 within
the zona matrix (Bleil and Wassarman, 1980a) and data have been
advanced suggesting a role for O-linked oligosaccharide side
chains (Bleil and Wassarman, 1980a; Florman and Wassarman,
1985). Different laboratories have implicated terminal a1,3galactose (Bleil and Wassarman, 1988) or N-acetylglucosamine
(Miller et al., 1992) in mediating this interaction. However, more
recent genetic studies have not con®rmed the primacy of ZP3 as a
sperm receptor (Rankin et al., 1998) and mice lacking either the
galactosyltransferase required for the addition of a1,3-galactose
(Thall et al., 1995), or the galactosyltransferase isoform thought
Mouse models for human reproduction
Figure 2. Maternal proteins affecting early development. During meiotic maturation, the oocyte genome becomes transcriptionally silent, fertilization occurs with
a transcriptionally inert sperm and activation of the embryonic genome does not occur until the transition between the 1 and 2-cell stages. Thus, events during the
latter stages of meiotic maturation and early embryogenesis must be controlled by pre-existing maternal factors which can be activated by a variety of mechanisms.
MPF (Maturation Promoting Factor) is required for meiotic maturation; MOS, a proto-oncogene, and MAPK (Mitogen Activated Protein Kinase) are required for
meiotic spindle formation; SPIN (SPINDLIN), present in growing oocytes, persists until the 4 cell stage of embryogenesis and is associated with the ®rst mitotic
spindle; HSF1 (Heat-shock Factor 1) is required for early embryogenesis; and embryos lacking MATER (Maternal Antigen That Embryos Require) do not progress
beyond the 2-cell stage.
to bind the terminal N-acetylglucosamine residue (Asano et al.,
1997; Lu and Shur, 1997), remain fertile.
Normally, human sperm will not bind to mouse oocytes
(Bedford, 1977). Therefore, to genetically determine if ZP3 was
responsible for the taxon-order speci®city of sperm binding,
transgenic mice expressing human ZP3 were established and bred
into a Zp3 null line (Rankin et al., 1998). The expression of
human ZP3 protein in mouse oocytes rescues the mouse Zp3 null
phenotype by restoring the integrity of the zona matrix. However,
there is no change in the speci®city of sperm binding: mouse
sperm bind and fertilize the `humanized' mouse oocyte and
human sperm do not bind despite the presence of human ZP3.
Given the importance ascribed to carbohydrate side chains in
sperm binding, it seemed possible that human ZP3 expressed in
mouse oocytes is functionally converted from human to mouse
speci®city by post-translational modi®cation. However, based on
mobility in sodium dodecyl sulphate±polyacrylamide gel electrophoresis, human ZP3 expressed in mouse oocytes is posttranslationally modi®ed to the same extent as native human ZP3
(64 kDa) and distinctly different from native mouse ZP3 (83
kDa). While unable to discount subtle post-translational modi®cations, it now seems more likely that zona components beyond
ZP3 are required to render human sperm binding. Mouse lines
expressing additional human zona proteins are in the process of
being evaluated.
Once the oocyte has been fertilized, cortical granules located in
the periphery exocytose into the perivitelline space. This process
modi®es the zona pellucida so that no more sperm bind and sperm
within the perivitelline space are unable to fuse with the oocyte's
plasma membrane. The zona modi®cation involves cleavage of
ZP2 into several N-terminal polypeptides (21±31 kDa) that
remain bound to the parental ZP2 by disulphide bonds (Bleil et
al., 1981; Greenhouse et al., 1999). Whether the cleavage of ZP2
is causative or re¯ective of the block to polyspermy remains to be
resolved. Moreover there may be other, yet to be described,
modi®cations of the zona matrix that are important for the block
to polyspermy.
Early embryogenesis
At fertilization, both male and female gametes are transcriptionally inert and the earliest stages of embryogenesis are dependent
on maternal components stored within the oocyte (Bachvarova
and De Leon, 1980; Rosenthal and Wilt, 1986; Paynton et al.,
1988; Stutz et al., 1998). While some maternal proteins are
immediately available for early development, others need to be
translated from dormant maternal mRNA after activation by
cytoplasmic polyadenylation (Huarte et al., 1987). Initially these
untranslated maternal mRNA are bound by cytoplasmic proteins,
making them inaccessible to the translation apparatus (Curtis et
al., 1995). Subsequent, post-translational modi®cations of RNA
binding proteins release mRNA and make them available for
polyadenylation and translation (Richter et al., 1990; Mendez et
al., 2000). Additional factors that bind to the 3¢ untranslated
region (UTR), including the nuclear polyadenylation signal
(AAUAAA) and the cytoplasmic polyadenylation element
(UUUUUAU), are then required for the correct temporal
translational control of these transcripts. These newly synthesized
maternal factors along with pre-existing proteins, some of which
have undergone post-translational modi®cations (phosphorylation, glycosylation, proteolytic processing), are responsible for the
early developmental events (Cascio and Wassarman, 1982;
Howlett and Bolton, 1985; Latham et al., 1991; Oh et al., 1997)
As embryonic development proceeds, maternal components
decay and the process of embryogenesis becomes increasingly
dependent on the expression of the embryonic genome. De-novo
embryonic gene transcription is ®rst detected in the male
pronucleus in the late 1-cell embryo (Bouniol et al., 1995), but
the major activation of the embryonic genome does not occur
until the 2-cell stage (Flach et al., 1982; Schultz, 1993). Many of
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the early events of development, including activation of
embryonic transcription, are mediated by maternal proteins, but
only a small number of maternal-effect genes have been identi®ed
in mammals (Figure 2).
SPINDLIN
Some proteins synthesized from maternal mRNA have relatively
long half-lives and can remain at detectable levels until the
morula stage of development (Pratt et al., 1983; Richoux et al.,
1991). However, other proteins are only expressed for a short
period in a stage-speci®c manner. For example, the ®rst cell
cleavage requires the phosphorylation of SPINDLIN (SPIN),
which is associated with the ®rst mitotic spindle formation (Oh et
al., 1997). The SPIN transcripts and their products are detected in
unfertilized oocytes and 2-cell embryos, but not in 8-cell
embryos. There are three different SPIN transcripts which have
the same open reading frame, but differ in their 3¢ UTR and the
length of their polyA tails. The shortest message (0.8 Kb) is
expressed in oocytes prior to fertilization whereas the other two
transcripts are more ubiquitously present. Unlike the two longer
transcripts, the 0.8 kb transcript has no cytoplasmic polyadenylation element (CPE) motif which suggests that the 3¢ UTR may
account for differences in translation (Oh et al., 2000).
Maternal Antigen That Embryos Require (MATER)
Recently, the gene encoding MATER was characterized and
mouse lines lacking the protein were established (Tong and
Nelson, 1999; Tong et al., 2000). While homozygous null Mater
males have normal fertility, females are sterile. These mice have
normal folliculogenesis and their ovulated eggs can be fertilized.
However, embryos derived from MATER-de®cient females do
not grow beyond the 2-cell stage and exhibit a decrease in
transcriptional activity. Normally, there are two distinct phases of
transcriptional activities, early and late, that can be discriminated
by the sensitivity to a-amanitin treatment, known to inhibit the
formation of mRNA precursors (Worrad et al., 1994; Worrad and
Schultz, 1997). A stage-speci®c protein, the transcriptionrequiring complex (TRC), is synthesized during the early phase
of zygotic gene expression (Conover et al., 1991). The TRC
complex has been detected in embryos generated by females
lacking MATER, albeit at only 60% of the normal amounts.
These results suggest that zygotic genome activation is initiated
(at least partially) in embryos lacking MATER during early
embryonic activation. Although the primary structure of MATER
has been deduced from full-length cDNA, little is known about its
function in early embryogenesis.
Heat-Shock Factor-1 (HSF1)
Heat-Shock Factor-1 (HSF1) is known to activate stress-inducible
genes such as Hsp70.1 which is among the ®rst zygotic genes to
be expressed after fertilization (Bensaude et al., 1983; Christians
et al., 1997). Mice lacking HSF1 proteins are viable, but females
are infertile due to failed preimplantation development (Christians
et al., 2000). Similar to oocytes de®cient in MATER, germ cells
from Hsf1 null females have normal folliculogenesis and can be
400
fertilized. However, the majority of embryos generated by HSF1de®cient females do not develop beyond the 1-cell stage. When
females lacking HSF1 are crossed with males that carry a Hsp70
promoter-luciferase transgene, E1.5 embryos exhibited luciferase
activity suggesting that at least some zygotic transcription activity
can be initiated in the absence of HSF1. Whether HSF1 is
required for complete activation of the zygotic genome or
embryonic survival remains to be determined.
Summary
Female germ cells are programmed for success. Using developmentally controlled, oocyte-speci®c genes, they ensure correct
prenatal sexual identity, growth and survival during folliculogenesis, successful fertilization and activation of the embryonic
genome. Mouse genetics have provided unique insights into the
function of multiple genes involved in these processes and will
serve as a springboard for future research. In particular, it will be
useful to further characterize the role of BMP4 and OCT4 in the
establishment of the female germ cell lineage and the mechanisms
by which DAZL1 preserves germ cells perinatally. While
signi®cant advances have been made in identifying oocytespeci®c factors that affect folliculogenesis (e.g. FIGa, GDF9,
BMP15, CX37) and meiotic maturation (e.g. MPF, MOS MAPK),
clearly additional genes are involved. The near completion of the
human and mouse genome projects offers the promise of
accelerated gene discovery. In addition to identifying the role of
individual genes, the use of high throughput genomic screens
holds forth the prospect of de®ning novel genetic pathways (e.g.
downstream targets of FIGa). Particularly exciting avenues of
research include evolving investigations into the role of maternal
effect genes (e.g. Spindlin, Mater, Hsf1) in early embryogenesis.
Induced null mutations and allelic series of mouse genes that
result in phenotypes affecting germ cell development and
folliculogenesis will continue to advance the boundaries of our
knowledge. Current technologies that emphasize genetic approaches in model systems should rapidly translate into a better
understanding of human biology.
Acknowledgements
We appreciate the critical reading of the manuscript by Drs Teruko Taketo,
Olga Epifano and Holly Davies and apologize to our colleagues whose work
was not cited because of space limitations. Portions of this review have been
covered in previous publications of the authors.
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