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First published online 22 August 2007
doi: 10.1242/dev.001107
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Review |
Division of Molecular Genetics and Development, and ARC Centre of Excellence in Biotechnology and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
* Author for correspondence (e-mail: p.koopman{at}imb.uq.edu.au)
SUMMARY
Although mammalian sex is determined genetically, the sex-specific development of germ cells as sperm or oocytes is initiated by cues provided by the gonadal environment. During embryogenesis, germ cells in an ovary enter meiosis, thereby committing to oogenesis. By contrast, germ cells in a testicular environment do not enter meiosis until puberty. Recent findings indicate that the key to this sex-specific timing of meiosis entry is the presence or absence of the signaling molecule retinoic acid. Although this knowledge clarifies a long-standing mystery in reproductive biology, it also poses many new questions, which we discuss in this review.
Introduction
As cells go, germ cells are undeniably idiosyncratic. The founder population of primordial germ cells (PGCs) is established remarkably far in advance of the functional differentiation of gametes, and the colonization of the gonads by PGCs involves a long and perilous journey. During this time, PGCs must retain the capacity to differentiate into either oocytes or sperm, depending on whether they end up in an ovary or a testis. Germ cells clearly play a unique role as the carriers of genetic information between generations. To fulfill this role, germ cells are able to partition their genetic material in such a way as to generate haploid cells via a unique type of cell division known as meiosis (see Box 1). Not surprisingly, the origins, properties and behavior of germ cells continue to fascinate developmental and reproductive biologists.
This review focuses on how mammalian germ cells are directed towards the
alternative pathways of oogenesis or spermatogenesis, and the role of retinoic
acid (RA), the active derivative of vitamin A, in this process. The sex
differentiation of germ cells is determined not by their chromosomal
constitution but by cues from their environment
(McLaren, 1995
;
McLaren, 2003). Recent studies
have shown that the initial choice of male or female identity is governed in
mice by exposure to RA in the fetal gonad
(Bowles et al., 2006;
Koubova et al., 2006). These
studies reported that, although RA induces germ cells to enter meiosis in the
ovary at around 13.5 days post coitum (dpc), its degradation protects germ
cells from entering meiosis in males at that time. We argue here that these
findings reconcile two substantial bodies of data that have led to opposing
theories about how germ cell sexual fate is specified. We also review evidence
that suggests that the role of RA might be reprised during the regulation of
entry of male germ cells into meiosis in the postnatal testis.
Germ cell specification, proliferation, migration and maturation
Much of our knowledge regarding germ cell behavior in mammals has been
gleaned from studies in mice. At around 7.2 dpc in mice, somatic signals
earmark a small cohort of proximal epiblast cells as potential germ cell
precursors (Ginsburg et al.,
1990; Lawson et al.,
1999; Lawson and Hage,
1994; Tam and Zhou,
1996; Ying et al.,
2000). This group of cells moves into the extraembryonic tissues
at the base of the allantois, where a second round of molecular selection
occurs, resulting in a group of about 45 cells that are identifiable as germ
cell precursors or PGCs (Lawson and Hage,
1994; Ohinata et al.,
2005; Saitou et al.,
2002; Tanaka and Matsui,
2002). PGCs proliferate rapidly and migrate anteriorly through the
elongating hindgut towards the future site of the primitive gonads, the
genital ridges. The PGCs colonize the genital ridges at around 10.5 to 11.5
dpc, just after these structures arise from the intermediate mesoderm and
somatic sex determination is underway. The movements of PGCs suggest that they
respond to an attractant that emanates from the genital ridges, possibly the
chemokine SDF1 (also known as CXCL12 - Mouse Genome Informatics) and/or the
growth factor kit ligand (KITL) (Farini et
al., 2007; Molyneaux et al.,
2001; Molyneaux et al.,
2003). PGCs then change their shape, become less motile and
continue to proliferate for 1-2 days, so that about 26,000 germ cells reside
in the gonads by 13.5 dpc (Donovan et al.,
1986; Tam and Snow,
1981).
| Box 1. Meiosis Gametes are haploid, and so are produced by reductive nuclear division of a diploid germ cell in a specialized process known as meiosis. Meiosis includes two cell divisions (meiosis I and meiosis II), the first with, and the second without, DNA replication. During prophase of meiosis I, each pair of homologous chromosomes aligns and is held together tightly by a meiosis-specific nucleoprotein structure known as the synaptonemal complex. As is the case for mitotic division, each chromosome duplicates by DNA replication, producing two sister chromatids. The pairing of chromosome homologs allows genetic recombination to occur, because non-sister chromatids of homologs can cross-over (forming `chiasmata') and exchange analogous fragments of DNA. Such a four-chromatid structure is called a bivalent. During metaphase of meiosis I, bivalents line up perpendicular to the spindle and at anaphase the pair of chromosomal homologs (each composed of two sister chromatids) break apart and move to opposite poles of the spindle, and division I of meiosis occurs. The two cells produced are still diploid in terms of the amount of DNA they contain, but they differ from normal diploid cells in that they have two near-identical copies of each chromosome - differing only where genetic recombination has occurred - rather than a paternal and a maternal copy of each chromosome. A second round of cell division, without further DNA replication, is necessary before haploid gametes are produced. In division II of meiosis (meiosis II), duplicated chromosomes align along a second spindle and sister chromatids separate to produce two cells with haploid DNA content. To summarize, each diploid cell entering meiosis undergoes one round of DNA replication followed by two rounds of cell division, potentially producing four genetically different haploid cells. In the male, this amounts to four spermatozoa but, in the female, only one functional gamete is ultimately produced, the other genetic material being lost in the form of polar bodies. The time required for each stage of meiosis differs greatly among species and between the sexes of a single species. In general, meiotic prophase I takes the longest time, ranging from days (e.g. in human males) to decades (e.g. in human females).
|
The first morphological evidence of sex-specific germ cell development is
seen at around 13.5 dpc (Fig.
1). At that time, in a developing mouse ovary, germ cells stop
proliferating and enter prophase of the first meiotic division, progressing
through leptonema, zygonema, pachynema and diplonema. At around the time of
birth, they then enter a specialized, prolonged arrest stage known as dictyate
(Speed, 1982). The oocytes
remain in this state until just before ovulation, at which point they complete
the first meiotic division, begin the second and arrest again. Meiosis is
completed only after fertilization.
|
;
McLaren, 1984). Primary
spermatocytes are seen as early as 5 days post natum (dpn), signifying that
some spermatogonia have entered meiosis. In terms of germ cell
differentiation, this stage in mice is equivalent to puberty in humans. The
primary spermatocytes then complete both meiotic divisions promptly to
generate spermatids, which mature further into functional gametes called
spermatozoa or sperm. In the male, waves of meiosis continue throughout life,
providing a continuous supply of sperm from spermatogonial stem cells at the
periphery of the testis cords. Somatic influences on sex-specific germ cell fate
What causes the sex-specific behavior of germ cells? Studies involving
XX
XY chimeras have shown that germ cells, whether XX or XY, enter
meiosis if they find themselves in a developing ovary, but avoid doing so in
the environment of a developing testis
(Evans et al., 1977;
Palmer and Burgoyne, 1991).
Therefore, the initial sex differentiation of a germ cell is determined not by
its chromosomal constitution, but by its environment
(McLaren, 1995;
McLaren, 2003). However, the
completion of meiosis and the formation of functional gametes are influenced
by the sex-chromosome composition of the germ cell
(Amleh et al., 2000;
Bradbury, 1983;
Burgoyne, 1987;
McLaren, 1981;
Park and Taketo, 2003;
Taketo-Hosotani et al.,
1989).
A well-accepted hypothesis to explain the effect of tissue environment on
germ cell fate has been that the developing testicular tissue produces a
meiosis-inhibiting factor (Buehr et al.,
1993; Francavilla and Zamboni,
1985; McLaren,
1984). This factor was supposedly produced at around 12.0 dpc by
immature Sertoli cells, the supporting somatic cells in the developing testis,
and considered likely to be a short-range diffusible factor
(McLaren and Buehr, 1990;
McLaren and Southee, 1997).
The mechanism by which meiosis is triggered in the ovary has been a subject of
considerable debate. The point at issue has been whether, in the developing
ovary, initial entry into meiosis occurs spontaneously and cell-autonomously,
perhaps regulated by a molecular clock
(Donovan et al., 1986;
McLaren and Southee, 1997;
Ohkubo et al., 1996), or
whether this step is induced by surrounding somatic tissue
(Byskov, 1974;
Byskov, 1975;
McLaren, 1984). These two
opposing theories will be discussed later, in the light of recent
findings.
Exposure to RA regulates entry into meiosis
Two recent studies (Bowles et al.,
2006; Koubova et al.,
2006) indicate that exposure to RA controls whether mouse fetal
germ cells enter meiosis or not. RA is a small, polar molecule that easily
diffuses through tissues and acts by binding to nuclear RA receptors (RARs,
which include the RAR
, ß and 
isotypes), which
heterodimerize with nuclear retinoid X receptors (RXR, ß and
) (Chambon, 1996;
Mark et al., 2006). RAR-RXR
dimers bind to RA-response elements (RAREs) and thereby control the expression
of RA-responsive genes (Chambon,
1996). RA has many known roles in morphogenesis, growth and
differentiation during vertebrate embryogenesis and organogenesis
(Mark et al., 2006).
The first clue that RA might play a role in female-specific gonadal
development came from male versus female gonad gene expression screens in
mice. In some screens, the gene Cyp26b1 was more highly expressed in
male than in female gonads, particularly at 13.5 dpc, the critical time at
which female, but not male, germ cells enter meiosis
(Bowles et al., 2000;
Menke and Page, 2002).
Cyp26b1 encodes a P450 enzyme, CYP26B1 (also known as P450RAI-2),
that acts by catabolizing all-trans RA into inactive metabolites
(White et al., 2000;
Yashiro et al., 2004). CYP26
enzymes act to regulate local levels of RA in several developmental contexts,
such as during central nervous system, inner ear, eye and limb patterning
(Hernandez et al., 2007;
Romand et al., 2006;
Sakai et al., 2004;
Yashiro et al., 2004).
Cyp26b1 transcripts are detectable in mouse gonads at 11.5 dpc, at
higher expression levels in males than females
(Bowles et al., 2006). After
11.5 dpc, Cyp26b1 expression is undetectable in female gonads but is
very high in male gonads. Expression is associated with Sertoli cells and some
interstitial cells, and peaks at around 13.5 dpc
(Bowles et al., 2006;
Menke and Page, 2002). This
profile of expression suggests that CYP26B1 might protect male gonads from the
actions of RA between 12.5 and 14.5 dpc, and matches that expected of the
postulated meiosis-inhibiting factor
(McLaren and Southee,
1997).
It is now clear that RA acts to initiate meiosis
(Bowles et al., 2006;
Koubova et al., 2006). First,
RA levels are higher in the female than the male mouse gonad at 13.5 dpc
(Bowles et al., 2006).
Furthermore, exogenous RA can induce XY germ cells in a cultured mouse fetal
testis to enter meiotic prophase (Bowles et
al., 2006; Koubova et al.,
2006), as judged by the histological detection of condensed
meiotic nuclei and the expression of three meiotic markers, named: stimulated
by retinoic acid gene 8 (Stra8), synaptonemal complex protein 3
(Sycp3) and dosage suppressor of mck1 homolog (Dmc1)
(Chuma and Nakatsuji, 2001;
Nakatsuji and Chuma, 2001;
Oulad-Abdelghani et al., 1996)
(see Table 1). Untreated XY
germ cells do not normally express Stra8, and express Sycp3
and Dmc1 weakly only (Chuma and
Nakatsuji, 2001; Menke et al.,
2003; Nakatsuji and Chuma,
2001). Finally, chemically antagonizing RARs in cultured mouse
fetal ovaries prevents XX germ cells from entering meiosis
(Bowles et al., 2006;
Koubova et al., 2006). These
findings complement earlier studies that showed that exogenous RA added to rat
XX germ cells in ex vivo organ culture accelerates their entry into meiosis
(Livera et al., 2000).
|
; Koubova et al.,
2006). Sycp3 and Dmc1 expression also increased,
indicating that these XY germ cells in the treated gonads are in the early
stages of meiosis I (Bowles et al.,
2006; Koubova et al.,
2006). When male gonads were cultured with both a CYP26 inhibitor
and an RAR panantagonist, Stra8 expression was not induced,
indicating that, in a developing male gonad, CYP26B1 functions to degrade RA,
which would otherwise act via RARs to upregulate Stra8 expression
(Koubova et al., 2006).
|
).
Cyp26b1-null mice die immediately after birth with multiple
abnormalities, including limb defects
(Yashiro et al., 2004). XY
gonads from Cyp26b1-null embryos showed upregulation of
Stra8 and Sycp3 expression at 13.5 dpc, demonstrating that
germ cells in the XY mutant embryos are entering meiotic prophase I at this
early stage, as if in a normal XX embryo
(Bowles et al., 2006). These
findings were recently extended by the analysis of a second
Cyp26b1-null line of mice
(MacLean et al., 2007); it was
found that, in the absence of CYP26B1, XY germ cells enter meiosis by 13.5 dpc
and proceed through meiotic prophase, with some reaching zygotene/pachytene,
as judged by histological staining and chromosome spread analysis. By birth,
virtually all germ cells were lost in Cyp26b1-null testes because of
progressive apoptosis (MacLean et al.,
2007). Importantly, these studies confirmed independently that RA
levels are increased in embryonic testes when CYP26B1 is not present. Using a
synthetic retinoid that cannot be degraded by CYP26B1, it was demonstrated
that the role of CYP26B1 in this system is to degrade RA, hence preventing it
from signaling, rather than to produce an active RA metabolite.
The role of CYP26B1 in germ cell development might not be limited to
preventing meiosis in the fetal testis. In Cyp26b1-null ovaries, the
wave of Stra8 expression appears to initiate earlier than is normal
(Bowles et al., 2006). Because
Cyp26b1 is expressed initially in the gonads of both sexes
(Bowles et al., 2006)
(Fig. 2), we surmise that, in
Cyp26b1-null XX gonads, complete absence of CYP26B1 might allow RA to
accumulate to a meiosis-inducing level earlier than in wild-type female
gonads. Therefore, Cyp26b1 expression might be relevant to the timing
of meiotic entry in germ cells of both sexes. It will be interesting to see
whether early entry into meiosis has any detrimental effect on
Cyp26b1-null XX germ cells.
What is the source of RA during urogenital development?
One question raised by these observations is whether RA is produced in the
developing fetal gonads or whether it comes from elsewhere in the developing
urogenital system. Bowles et al. have provided several lines of evidence
indicating that RA is not synthesized in the gonads themselves, but rather by
the mesonephroi to which the gonads are attached
(Bowles et al., 2006). The
gonad begins to grow out from the mesonephros at around 10 dpc, and the two
organs remain in contact for some time during development. Using reporter mice
and cells in which the reporter gene lacZ is driven by an RARE
(RARE-lacZ mice), it was demonstrated that the ducts and tubules of
the mesonephroi of both sexes produce RA
(Bowles et al., 2006). In
concordance with this, Aldh1a2, which encodes the enzyme RALDH2 and
is most commonly associated with RA production in the embryo, is highly
expressed in the mesonephros from at least 10.5 dpc
(Bowles et al., 2006). The
complementary patterns of an RA-synthesizing enzyme in the mesonephros and an
RA-catabolyzing enzyme in the attached male gonad indicates that an RA
source/sink system exists, analogous to that in the developing retina and
inner ear (McCaffery et al.,
1999; Romand et al.,
2006).
Several studies have shown that germ cells in the developing ovary enter
meiosis in an anterior-to-posterior wave and not, as might have been expected,
simultaneously or stochastically (Bullejos
and Koopman, 2004; Menke et
al., 2003; Yao et al.,
2003). This wave is evident from Stra8 expression, which
begins at 
12.5 dpc in the anterior part of the gonad and extinguishes at
16.5 dpc at the posterior end (Menke
et al., 2003) (Fig.
3A). This pattern is also seen, about 1 day later, with the
upregulation of the meiosis marker Sycp3 and the downregulation of
the pluripotency marker POU domain, class 5, transcription factor 1
(Pou5f1, Oct3/4) (Bullejos and
Koopman, 2004; Yao et al.,
2003) (Fig. 3B).
Sycp3 encodes a major structural protein of the synaptonemal complex
(see Box 1) and is considered
to be a specific marker of meiotic germ cells
(Chuma and Nakatsuji, 2001;
Nakatsuji and Chuma, 2001),
whereas Pou5f1 encodes a transcription factor that represses
differentiation genes (Pesce et al.,
1998). In addition, Pou5f1 promotes germ cell survival
(Kehler et al., 2004). Because
there is no evidence that germ cells colonize the anterior end of the gonad
first (Molyneaux et al.,
2001), this slow anterior-to-posterior wave of entry into meiosis
is consistent with meiosis being induced, rather than being automatic, in germ
cells.
|
;
Karl and Capel, 1995)
(Fig. 2). If so, the anterior
germ cells would be the first to be exposed to RA. Alternatively, cells might
migrate from the mesonephric tubules into the anterior tip of the gonad and
emit RA, producing a gradient that might lead to the observed wave of
expression of meiosis markers.
When gonads and mesonephroi were explanted from RARE-lacZ mouse
embryos, ß-galactosidase staining confirmed that RA is more concentrated
at the anterior than at the posterior end of the gonads at 12.5-14.5 dpc
(Bowles et al., 2006). It
remains to be seen whether the developing ovary can be separated
experimentally from the mesonephros early and cleanly enough to test the
importance of the mesonephros in regulating meiosis. Proof that the
mesonephros is the source of RA would require the production and analysis of
mesonephros-specific Aldh1a2-deleted mice
(Vermot et al., 2006); total
ablation of Aldh1a2 is lethal by 10.5 dpc
(Niederreither et al.,
1999).
A model summarizing our current understanding of the regulation of germ cell entry into meiosis, and the role of RA in this process in mouse fetal gonads, is shown in Fig. 2.
Reconciling new findings with established theories
The issue of whether meiosis is induced or whether it initiates spontaneously and cell-autonomously has been contentious, because both arguments are supported by convincing experimental data. Here, we examine the evidence supporting each of the two main theories and then re-evaluate them in the light of recent findings.
The `intrinsic clock' theory
Germ cells that accidentally colonize non-gonadal locations, such as the
adrenal gland, enter meiosis as they would in the developing ovary
(Upadhyay and Zamboni, 1982;
Zamboni and Upadhyay, 1983).
Similarly, XY germ cells isolated at 10.5 or 11.5 dpc, combined with
dissociated embryonic lung cells and cultured for several days, also commence
meiosis (McLaren and Southee,
1997). In the ectopic location of the mesonephros, XY germ cells
tend to enter meiosis (Byskov,
1978c; McLaren,
1983; McLaren,
1984). Because it appeared that meiosis could occur in almost any
tissue environment, it was hypothesized that this pathway might be automatic
in germ cells of a certain age. Thus, timing of entry into meiosis might be
determined by the number of mitoses occurring after the germ cell lineage was
established or had started to migrate
(McLaren, 2003;
McLaren and Southee, 1997;
Ohkubo et al., 1996).
This `intrinsic clock' theory (Donovan
et al., 1986) was supported by studies of cultured germ cells
(Chuma and Nakatsuji, 2001;
Nakatsuji and Chuma, 2001).
When 10.5 dpc mouse gonad-mesonephros complexes, or 11.5 dpc gonads, are
dissociated and cultured on feeder cells with 20% fetal calf serum, germ cells
of either sex can reach the leptotene stage of the first meiotic division
(Chuma and Nakatsuji, 2001).
Germ cells isolated prior to entry into the gonads also enter meiosis when
cultured, supporting the theory that a signal from the gonadal cells is not
required to initiate meiosis (Chuma and
Nakatsuji, 2001).
A corollary of this hypothesis is that an overriding mechanism must operate
in the fetal testis to actively block entry into meiosis
(Buehr et al., 1993;
Francavilla and Zamboni, 1985;
McLaren, 1984). The production
of this meiosis-inhibiting factor evidently depended on the structural
integrity of the testis cords, because dissociation and re-aggregation of
fetal urogenital ridges allows germ cells to enter into meiosis
(McLaren and Southee,
1997).
The meiosis-inducing-substance theory
Despite the obvious attractions of the intrinsic clock theory, a large and
long-standing body of experimental evidence has supported the existence of a
somatically derived, meiosis-inducing substance. For example, meiosis in XY
germ cells can be induced by culturing male fetal gonads for 6 days with
conditioned media from cultured ovaries or testes in which meiosis is
occurring (Byskov et al.,
1993; Byskov and Saxen,
1976) or in follicular fluid taken from pre-ovulatory follicles
(Westergaard et al., 1984).
Similarly, conditioned media from cultured fetal epididymides of fetal mice
(Byskov, 1978a), pubertal mice
or bulls (Grinsted et al.,
1979), or fetal and adult humans
(Grinsted and Byskov, 1981),
can also induce mouse XY fetal germ cells to undergo meiosis.
In particular, meiosis appeared to be induced by a factor secreted from a
region known as the rete ovarii (Byskov,
1974). The rete ovarii develops from mesonephric cells that
migrate into the developing gonad, and includes the mesonephric tubules and
their connections with the anterior end of the gonad
(Byskov, 1978b). When the
cranial half of 12.0 dpc fetal mouse ovaries, with the extra-ovarian rete
tubules and mesonephros still attached, is grafted into nude mice, the germ
cells enter meiosis and continue to develop normally. By contrast, when the
caudal part, without associated rete tubules, is grafted, germ cells do not
enter meiosis and remain as oogonia
(Byskov, 1974). In other
species, such as cats, minks and ferrets, meiosis begins in the part of the
ovary that is in closest contact with mesonephric tissue
(Byskov, 1975). Fetal
testicular germ cells that happen to have been excluded from testis cords and
instead end up located near the connecting rete cords can enter meiosis,
leading to the conclusion that male, as well as female, rete can induce
meiosis but that germ cells are normally protected from this effect in the
developing testes (Byskov,
1978c; Byskov,
1986).
Byskov et al. attempted to characterize meiosis-inducing substances from
human follicular fluid and bull testes
(Byskov et al., 1995). Perhaps
because they assayed resumption rather than the initiation of meiosis, their
experiments led them to isolate naturally occurring sterols that are
intermediates of the cholesterol biosynthetic pathway: these appear not to
trigger initial entry into meiosis (Byskov
et al., 1998).
In view of the considerable evidence supporting the intrinsic clock theory, and given that no meiosis-inducing substance was identified in recent decades, the existence of a meiosis-inducing substance was largely discredited. Researchers instead concentrated on finding the male-specific meiosis-inhibiting substance.
A model for sex-specific regulation of germ cell fate
So, which theory is correct - active induction of meiosis, or spontaneous
entry of fetal germ cells into meiosis unless prevented by a
meiosis-inhibiting factor? The answer is neither and both: the recent
identification of the RA-CYP26B1 system suggests a model that includes
elements of both theories (Fig.
2). RA can, and normally does, induce fetal germ cell meiosis
(Bowles et al., 2006;
Koubova et al., 2006),
indicating that meiosis is actively induced rather than occurring
spontaneously via an intrinsic clock mechanism. When Cyp26b1 is
absent from the fetal testis, germ cells enter meiosis
(Bowles et al., 2006;
MacLean et al., 2007). Hence,
CYP26B1 is a meiosis-inhibiting factor, if not the meiosis-inhibiting factor.
The new model also includes a feature not previously predicted - that the
meiosis-inhibiting factor controls not just the avoidance of meiosis in the
fetal testis, but also the timing of entry into meiosis in the ovary.
How does this model explain the apparently spontaneous entry of ectopic or
cultured fetal germ cells into meiosis, which formed the basis of the
intrinsic clock theory? It seems likely that those germ cells enter meiosis
because of exposure to RA. First, RA is present in many embryonic tissues,
including the lungs, adrenals and mesonephroi
(Horton and Maden, 1995;
Rossant et al., 1991). The
concentration of all-trans RA is around 4x10-8 M in visceral
tissues at 10.5 and 13.5 dpc (Horton and
Maden, 1995), and we find that as little as
1x10-8 M RA can induce Stra8 expression in isolated
11.5 dpc germ cells in vitro (J.B. and P.K., unpublished data). Secondly, in
experiments in which dissociated gonadal cells have been cultured in
isolation, or co-cultured with dissociated embryonic lung cells, the bovine
serum in the media probably provides sufficient RA to drive meiotic induction.
Media supplemented with 10% fetal bovine serum is estimated to contain
3.6x10-8 M RA (Fuchs and
Green, 1981). It remains to be seen whether `spontaneous' entry
into meiosis in cell culture can be inhibited by blocking RARs.
The observation that dissociation/re-aggregation of fetal male urogenital
ridges is permissive for meiosis (McLaren
and Southee, 1997) is most likely to be explained by the
juxtaposition of germ cells with RA-producing mesonephric cells
(Bowles et al., 2006), and not
by the loss of a meiosis-inhibiting factor, as was originally hypothesized. In
the intact fetal testis, germ cells are surrounded by Sertoli cells in cords,
and this arrangement might protect germ cells from RA
(Fig. 2). CYP26B1 is produced
by Sertoli cells (Bowles et al.,
2006) and, because this enzyme acts within the cytoplasm of the
cells in which it is produced, the cord structure could physically shield germ
cells from any RA in the interstitium.
A pillar of the intrinsic clock theory is that a short-range signaling
molecule emanates from somatic (probably Sertoli) cells of the developing
testis and prevents meiosis. Although we now know that a testis-derived
meiosis inhibitor acts in fetal mice, this molecule is not a secreted signal
but rather the cytosolic enzyme CYP26B1
(Bowles et al., 2006;
Koubova et al., 2006). So, the
new paradigm of regulation of germ cell fate in mice by a system of RA
induction of meiosis, combined with the testis-specific expression of CYP26B1
to prevent this induction in males, combines elements of both of the previous
theories on germ cell-fate specification. It also raises several new
questions.
Why might a meiosis-inducing substance, such as RA, be produced in male and
female reproductive tissue? RA is widespread and regulates many developmental
processes (Rossant et al.,
1991), and it would seem imprudent to rely on sex-specific
exposure of germ cells to RA to ensure that entry into meiosis occurs only in
the ovary. Instead, a pathway of gene regulation set in motion by SRY and
leading to Cyp26b1 expression provides a robust, male-specific system
of eliminating RA only in male gonads.
Does RA provide the only signal that stimulates germ cell entry into
meiosis in the mouse fetus? By chemically antagonizing RARs in cultured mouse
fetal ovaries, germ cells are prevented from entering meiosis
(Bowles et al., 2006;
Koubova et al., 2006),
suggesting that RA is essential and that other pathways either do not exist,
or are insufficient to induce meiosis. It remains possible that male
developing gonads have a supporting or back-up mechanism, in addition to RA
degradation by CYP26B1, to prevent germ cells from entering meiosis.
Certainly, the developing male gonads have mechanisms for dealing with germ
cells that inadvertently enter and progress through meiosis: in
Cyp26b1-null fetal testes, meiotic markers are upregulated in germ
cells, but meiotic germ cells subsequently undergo apoptosis
(MacLean et al., 2007).
Is RA instructive or merely permissive for germ cell entry into meiosis?
The data suggest that it is instructive, because the blocking of RARs results
in downregulation of meiosis markers, especially of Stra8
(Bowles et al., 2006;
Koubova et al., 2006), which
encodes a protein known to be essential for meiotic initiation
(Baltus et al., 2006). If RA is
instructive, then it should first be absent (before meiotic induction) and
then present (when meiosis is induced). Direct measurements of RA levels at
various times of development in the ovary have not been made. However, it is
possible to infer that RA levels increase with time, because Cyp26b1
expression in the fetal ovary disappears between 11.5 dpc and 12.5 dpc
(Bowles et al., 2006).
Moreover, the pattern of entry into meiosis of XX germ cells is consistent
with an instructive signal coming predominantly from the anterior end of the
gonad-mesonephros complex. A further distinction between induction and
permission might be found in the molecular details of the relationship between
RA and the engagement of the meiotic machinery, to which we now turn.
How does RA induce meiosis?
Because the upregulation of meiotic markers and the downregulation of
Pou5f1 are inhibited by RAR antagonists in fetal ovary culture, RA
must signal through RARs to induce meiosis
(Bowles et al., 2006;
Koubova et al., 2006).
Moreover, RAR agonists selective for each of the three RAR isotypes can induce
Stra8 expression in cultured ex vivo testes, suggesting that RA can
signal through any RAR in this system
(Koubova et al., 2006). At
least some RARs and RXRs are expressed by germ cells at the relevant stage of
development, but somatic cells also express these receptors
(Boulogne et al., 1999;
Bowles et al., 2006;
Li and Kim, 2004;
Morita and Tilly, 1999;
Vernet et al., 2006) so it is
theoretically possible that RA acts on somatic cells, which then send a
secondary signal to germ cells to induce meiosis.
Assuming that RA acts directly on germ cells, what are the molecular steps
between the reception of the RA ligand and the orchestration of a meiotic
response? Germ cells do not initiate meiosis in Stra8-null mice
(Baltus et al., 2006), so RA
must trigger meiosis by inducing the cytoplasmic protein STRA8
(Oulad-Abdelghani et al.,
1996). Stra8 was first identified as an RA target gene
(Bouillet et al., 1995;
Oulad-Abdelghani et al.,
1996), although whether it is regulated directly or indirectly by
RA is not known. Because treatment of embryonal carcinoma (EC) cells (stem
cells of teratocarcinomas) with RA upregulates Stra8 expression in
less than 2 hours (Oulad-Abdelghani et
al., 1996), RA might bind as a ligand to an RAR-RXR heterodimer
that then recognizes and binds an RARE sequence upstream of Stra8.
The RXR-RAR isotype combination plays the major role in mediating
Stra8 induction (Chiba et al.,
1997). Nonetheless, an indirect pathway involving some
intermediate transcription factor(s) remains possible. In some circumstances,
unliganded RAR-RXR complexes bind and repress the transcription of targets
until an RA ligand becomes available
(Weston et al., 2003). This
mechanism might also underlie the regulation of Stra8 and of any
other target genes in this system.
In germ cells of the Stra8-null mouse fetal ovary, cohesion
proteins are not produced, the synaptonemal complex (see
Box 1) does not form and DNA
double-strand breaks appear not to form or repair. However, pre-meiotic
chromosome condensations are observed
(Baltus et al., 2006). The
presence of such chromosome condensation supports the idea that germ cells in
a developing gonad of either sex are poised to respond to signals from the
environment, whether they be inductive or preventative
(McLaren and Southee, 1997).
Although XY germ cells do not normally enter meiosis during fetal development,
the low level expression of meiosis-associated genes, such as Sycp3
and Dmc1, may indicate that all germ cells prepare to enter meiosis
after their arrival in the genital ridge
(Byskov, 1978c;
Chuma and Nakatsuji, 2001;
Di Carlo et al., 2000;
Nakatsuji and Chuma, 2001).
This preparation must be independent of any RA effect because Cyp26b1
is expressed in the gonads of both sexes from an early time-point and because
there is no reported expression of Stra8 in the male developing gonad
at 12.5 dpc or earlier. RA might directly or indirectly upregulate
Stra8 expression, leading to the upregulation of other
meiosis-associated genes. Although we now have good evidence that STRA8 is
necessary for entry into meiotic prophase
(Baltus et al., 2006), the
cellular function of the protein is unknown.
Even though RA is widespread throughout the embryo, it seems that
Stra8 is never expressed in somatic cells
(Oulad-Abdelghani et al.,
1996). Possibly, RA is only able to upregulate Stra8
expression if a cell is in a specific epigenetic configuration
(Seki et al., 2005). In
addition, male and female patterns of DNA methylation or histone modification
might be mediated by additional sex-specific factors
(Matsui and Hayashi, 2007)
underlying, for example, the failure of XY germ cells to survive and progress
past pachytene in an XX gonadal environment.
When germ cells in a fetal mouse ovary begin to express Stra8,
they downregulate the pluripotency marker Pou5f1
(Menke et al., 2003). Perhaps
RA has a direct or indirect effect on Pou5f1 transcription; various
studies have linked RA-induced differentiation with the downregulation of
Pou5f1 in ES and EC cells
(Okamoto et al., 1990;
Rosner et al., 1990;
Scholer et al., 1989). It
appears that RA, directly via RARs or indirectly via molecules such as
germ-cell nuclear factor (GCNF or NR6A1, an orphan nuclear receptor), can
affect Pou5f1 transcription
(Fuhrmann et al., 2001;
Gu et al., 2005;
Minucci et al., 1996;
Pikarsky et al., 1994). The
further study of the distal and proximal enhancers (DE/PE) and the TATA-less
proximal promoter of Pou5f1 might clarify this point; in particular,
the DE site is thought to regulate Pou5f1 expression in migratory and
postmigratory germ cells (Yeom et al.,
1996).
Does RA induce meiosis in the pubertal testis?
Parsimony suggests that meiosis might be induced by similar mechanisms in
prenatal XX germ cells and postnatal XY germ cells. This might indeed be the
case, because genetic deletion of Stra8 precludes germ cells of
either sex progressing into prophase of meiosis I
(Baltus et al., 2006). Also,
the observation that media conditioned for 24 hours with minced adult mouse
testes can induce XY germ cells in a fetal testis to enter meiosis
(Byskov et al., 1993) further
supports idea of a common meiosis inducer in both sexes.
In male mice, the first meiotic entry at male puberty is followed by a
self-perpetuating cycle of meiotic initiation in germline stem cells. It is
not known how the initial round of meiosis, or later rounds, are triggered.
The expression profile of Stra8 in postnatal and adult mouse testes
is consistent with RA being involved in both events in males: in both
pre-pubertal and adult male mice, Stra8 is expressed by spermatogonia
and, possibly, by preleptotene-stage spermatocytes immediately prior to entry
into meiosis (Oulad-Abdelghani et al.,
1996). Furthermore, in sections of adult mouse testes,
Stra8 is highly expressed in basal non-somatic cells of some tubules,
and weakly or not at all in others, suggesting that its expression is
restricted to a pre-meiotic stage of the spermatogenic cycle
(Oulad-Abdelghani et al.,
1996).
In mice (McCarthy and Cerecedo,
1952) and rats (Thompson et
al., 1964), an association between vitamin A deficiency (VAD) and
male infertility is well-known. In the seminiferous tubules of VAD mice, germ
cells degenerate and only type A spermatogonia (male germline stem or early
differentiating pre-meiotic cells) remain
(van Pelt and de Rooij,
1990a). The situation is similar in VAD rats, but, in addition to
type A spermatogonia, the slightly more differentiated forms - type B
spermatogonia and preleptotene spermatocytes - are also found
(Huang and Hembree, 1979;
van Pelt and de Rooij, 1990b),
and when retinol or large doses of RA are provided to VAD rats and mice,
meiosis resumes promptly and synchronously
(Morales and Griswold, 1987;
van Pelt and de Rooij, 1990a;
van Pelt and de Rooij, 1991).
Recently, it was noted that the type A spermatogonia that remain in VAD adult
male mice differ from their wild-type counterparts in that they do not express
Stra8 (Ghyselinck et al.,
2006). Expression of Stra8 is restored when VAD mice are
given RA (Ghyselinck et al.,
2006; Koubova et al.,
2006).
|
). In the
early postnatal period (1-20 dpn), RA-synthesizing enzymes are expressed in
Sertoli cells, and RARs and RA-binding proteins are expressed by germ cells,
consistent with a role for RA in driving meiosis postnatally
(Fig. 4). RA-degrading enzymes
(CYP26A1, CYP26B1 and CYP26C1) are produced in peritubular myoid cells that
line the outer surface of the seminiferous tubules, separating them from the
circulation (Vernet et al.,
2006). Undifferentiated spermatogonia that are found closest to
the Sertoli cells were found to express the RA target gene Stra8
(Vernet et al., 2006).
These observations lead us to propose a model in which RA acts to induce
meiosis in the pre-pubertal male testis
(Fig. 4). We postulate that
retinol (but not RA, which is degraded by CYP26 enzymes) passes freely from
the circulation through the barrier of peritubular myoid cells into the
Sertoli cells. There, the final two steps of RA production could be carried
out under the control of alcohol dehydrogenases (retinol to retinal)
(Deltour et al., 1997) and
RALDH1/RALDH2 (retinal to RA). RA produced by the Sertoli cells could act in a
paracrine manner on adjacent pre-meiotic germ cells, ranging in stages of
maturity from type A spermatogonia through to preleptotene spermatocytes, all
of which express RARs (Vernet et al.,
2006). The pre-meiotic germ cells could then respond to RA by
expressing Stra8, thereby triggering the first round of meiosis. The
observation of robust expression of the cellular RA-binding protein CRABP1 in
all spermatogonia and in no other cell type of the testis
(Vernet et al., 2006) supports
the theory that RA has a function in one or more of the transitions up to and
including meiotic prophase. By contrast, expression of cellular
retinol-binding protein (CRBP1) in Sertoli cells suggests that they have the
capacity to store retinol (Zhai et al.,
1997). The catabolic barrier of CYP26 enzymes produced by
peritubular myoid cells, which surround and isolate the seminiferous tubule
(see Fig. 4G), might explain
the observation that the treatment of VAD mice with retinol restores
fertility, but treatment with RA is far less effective
(van Pelt and de Rooij,
1991).
In summary, we suggest that RA is probably produced by Sertoli cells in the postnatal mouse testis, and delivered in a juxtacrine fashion to spermatogonia, which then enter meiosis. If this is correct, the timing, site of production and means of delivery of RA to the germ cells differs in males and females, even though the effect - entry into meiosis via the upregulation of Stra8 expression - is conserved.
Conclusions
Available evidence indicates that RA stimulates germ cells to enter meiosis in the developing mouse ovary, and that it might also regulate meiotic progression in the pubertal testis. During male embryogenesis, CYP26B1 acts to remove RA and so functions as a meiosis-inhibiting factor. Experimental observations involving the addition or functional blockade of RA function in mouse fetal gonads indicate that RA is both necessary and sufficient to trigger the initial transition from mitosis to meiosis in germ cells of appropriate maturity. Evidently, RA induces meiosis via direct or indirect upregulation of Stra8 expression in fetal germ cells.
Mouse fetal testes and ovaries are remarkably different in structure; in
the male gonad, germ cells are enclosed in testis cords, whereas there is far
less organization in the ovary. Hence, it is possible that the system of
preventing meiosis in fetal testes by RA degradation is assisted by the
physical shielding provided by this compartmentalization. If and when germ
cells do enter meiosis in a developing testis, whether occasionally in nature
or induced in experimental situations, these cells are eliminated by apoptosis
(MacLean et al., 2007;
Yao et al., 2003). A
multi-level system that guards against meiosis in fetal male germ cells might
be important for ensuring the normal somatic development of the testes,
because meiotic germ cells probably produce signaling factors appropriate for
ovarian but not testicular development
(McLaren, 1991). Also, because
meiotic germ cells apoptose in the fetal testis, avoidance of meiosis would
maximize fertility.
The recent identification of a role for RA in the initiation of meiosis adds much to our understanding of sex-specific germ cell development in mammals, and will influence the approaches used to study the mechanism of meiosis and its somatic control. Many new questions have arisen based on these findings, opening up new lines of investigation. As yet, there are no clear answers to the questions of why is meiotic division specific to germ cells, what defines the window of competence of germ cells to respond to RA and how is RA signaling used to engage the meiotic machinery? With the current intense interest in the regulation of germ cell behavior among reproductive and developmental biologists, answers to these questions will be keenly sought.
ACKNOWLEDGMENTS
We dedicate this review to our friend and mentor Anne McLaren. This work was supported by research grants from the Australian Research Council (ARC), and National Health and Medical Research Council of Australia. P.K. is a Professorial Research Fellow of the ARC.
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