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From the * Laboratory of Genetics, NIA-IRP,
Baltimore, Maryland; División
Genética, Centro de Investigación Biomédica de Occidente,
CMNO-IMSS, Guadalajara, México; Unita'
di Genetica Medica, Universita' di Modena, Modena, Italy; and
Istituto di Neurogenetica e Neurofarmacologia,
Consiglio Nazionale delle Ricerche, Cagliari, Italy.
| Correspondence to: Dr David Schlessinger, Laboratory of Genetics, National Institute on Aging, 251 Bayview Blvd, Baltimore, MD 21224 (e-mail: SchlessingerD{at}mail.nih.gov). |
| Received for publication May 5, 2009; accepted for publication September 15, 2009. |
The discovery that the SRY gene induces male sex in humans and
other mammals led to speculation about a possible equivalent for female sex.
But females are proving to be more complicated. Several master genes appear to
be autonomously involved, and female sex determination seems to remain
relatively labile. Partial loss of function of the transcription factor
FOXL2 leads to premature ovarian failure in women; and in animal
models, Foxl2 is required for folliculogenesis as well as for
maintenance, and possibly induction, of female sex determination. In the germ
line, oocytes apparently form normally even in the absence of Foxl2,
dependent on genes that include female-specific factors such as
Fig-alpha, Nobox, etc. In the soma, ablation of
Foxl2 or the independently expressed gene Wnt4 (likely
downstream of Rspo1) can produce partial testis differentiation in XX
mice, and the double knockout results in the formation of tubules and
spermatogonia. This indicates that at least 2 autonomous ovarian pathways are
required to antagonize testis differentiation in females, a finding that is
being increasingly corroborated by studies in goats and nonmammalian
vertebrates. In recent expression profiling of mouse ovaries that lack
Foxl2 alone or in combination with Wnt4 or
Kit/c-Kit, we found that following Foxl2 loss,
early testis genes (including the downstream effector of Sry,
Sox9) and several novel ovarian genes were consistently dysregulated
during embryo-fetal development. The results support the proposal of
dose-dependent Foxl2 function and antitestis action. A partial
working model for somatic development and sex determination is presented in
which Sox9 is a direct antagonist of Foxl2 in the supporting
cell lineage.
Key words: Sex determination, ovary, testis, Foxl2, sex reversal, gonadal development
In males, the Y-linked male signal for testis determination, the "master gene" Sry or its downstream effector Sox9, is adequate to catalyze a powerful cascade leading from the bipotential gonad to the testis and spermatocytes (Koopman et al, 1991; Vidal et al, 2001). In females (XX or XO), in the absence of the male signal, development of the bipotential gonad is rather directed toward the ovary. However, studies in a number of laboratories have increasingly shown that in contrast to the testis, in which one gene can determine the sex of both germ cells and soma, in the ovary, there is no obvious single peremptory gene (represented by question marks in the schematic of Figure 1; and see following). Instead, a cohort of master genes are responsible in parallel for specific lineages: the partially defined pathways lead, more or less independently, to oocytes or to various female somatic cell types (Jeays-Ward et al, 2003; Kim et al, 2006; Parma et al, 2006; Maatouk et al, 2008; Tomizuka et al, 2008; Kocer et al, 2009). We focus here on our work with Foxl2 (boxed in Figure 1), a winged helix forkhead transcription factor that is not active in the testis but is specifically expressed in the granulosa cell lineage and is indispensible for ovary histogenesis (Loffler et al, 2003; Ottolenghi et al, 2005).
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The Foxl2 gene was first identified as mutated in a syndrome involving risk of premature ovarian failure (as well as an eyelid malformation, blepharophimosis/ptosis/epicanthus inversus syndrome [BPES]; Crisponi et al, 2001). Women who have loss of function of one allele of the gene are prone to early menopause. The primary point where Foxl2 acts was clear in a mouse model in which the gene was completely ablated (Uda et al, 2004). In the knockout, the fetal ovary is blocked in development. Follicle formation fails completely, and no steroid-forming cells or specialized vasculature forms. This accounts for defective or deregulated growth of somatic cells and oocytes, respectively (Schmidt et al, 2004; Uda et al, 2004). The actions of Foxl2 are characteristically relatively independent of other pathways, as shown in Figure 1. In particular, the expression of Foxl2 occurs whether or not oocytes are present (Figure 2), and, conversely, oocytes seem to form and enter meiosis indifferently to the absence of Foxl2 (Ottolenghi et al, 2005), although gene expression profiling suggests that the timing of meiosis is somewhat delayed (Garcia-Ortiz et al, 2009, and data not shown).
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Comparable results for other "modular" genes involved in ovary formation have been reported, particularly for Rspo1 and Wnt4 for somatic lineages and Lhx8 for oocytes (Choi et al, 2008; and see following). In all of these cases, knockout models have been compared by our group and others to assess the requirement of each gene for the expression of others. The compilation of expression profiling data has facilitated the inference of a possible gene regulatory network, including the identification of additional candidate genes with putatively independent functions in development and sex determination (Garcia-Ortiz et al, 2009).
Extent of Irreversibility of Sex Determination
In contrast to testis, not only does the ovary have different master genes
in different cell lineages, but ovarian somatic sex remains relatively labile,
with the potential to switch to a testis state. Traditionally, the process of
secondary partial sex reversal affecting the ovarian soma around birth or
later in life has been regarded as distinct from primary sex reversal
(Jost, 1972;
Burgoyne, 1988). Indeed,
several factors, such as loss of oocytes or excess anti-Müllerian
hormone, have been repeatedly implicated in late-onset partial anomalies, but
have never led to complete early sex reversal
(Lyet et al, 1995;
Guigon and Magre, 2006). By
contrast, we have shown that Foxl2 mutations affect both processes in
animal models, suggesting that the maintenance of female sex determination in
ovarian somatic cells may rely on the continuous expression of critical genes
that include Foxl2.
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In fact, from a series of results that initially seemed surprising, the loss of any of a plethora of early- or late-acting female genes, such as Foxl2 or the estrogen receptors, induces ovary-to-testis sex reversal in one or multiple somatic cell lineages at various time points after birth (eg, Crumeyrolle-Arias and Aschheim, 1981; Taketo-Hosotani et al, 1985; Couse et al, 1999; Guigon et al, 2005). In addition to representing a case of cell fate choice with alternative commitments, sex determination seems to assign opposed degrees of commitment to homologous cell lineages. In this sense, the mechanism of sex determination could itself be sexually dimorphic.
This might explain why testis tubules apparently never form ovarian follicle–like alternatives, though the structures can form together and stay more or less intermingled in true hermaphrodites. Nevertheless, partial derepression of female genes has been reported in neoplastic conditions in the testis (Ottolenghi et al, 2007b; Kalfa et al, 2008), and a slight up-regulation of Rspo1 and Wnt4 was recently reported in conditional knockout mice lacking both Sox9 and Sox8 (Barrionuevo et al, 2009). Although Rspo1 and Wnt4 are involved in female sex determination, they are expressed at high levels in bipotential gonads as well, and maintain low levels of expression in normal testes. Therefore, they do not represent unambiguous markers of male-to-female sex reversal, and a case of dedifferentiation of somatic cells (rather than transdifferentiation of male into female sex) cannot be ruled out. This would thus be similar to the model of conditional inactivation of the Wilms tumor gene, Wt1, which also involved loss of Sox9 and Sox8 expression during fetal life without sex reversal (Gao et al, 2006).
Future studies should reveal whether specific female markers like Foxl2 are also derepressed in testes that are deficient for male sex–determining genes. This would imply that secondary sex reversal can occur in testes as well as ovaries; and in both cases, the event would follow the disruption of sex-determining genes, which thus function after the time of sex determination and perhaps throughout life in both sexes. But even if that is so, molecular anomalies suggestive of sex reversal have not been associated with any histologically detectable reprogramming in the testes when male sex–determining genes were ablated. This contrasts with the ability of follicle cells to redifferentiate toward a testis tubule morphology at any time during ovary differentiation and maturation (see preceding and Ottolenghi et al, 2007b). Nevertheless, any such cases of molecular secondary male-to-female sex reversal may assist in the study of infertility associated with very little specific testis morphological anomaly or dysfunction. Dysfunction may include the so-called testicular dysgenesis syndrome that has embryo-fetal origin and shows complicated phenotypic expression (reviewed by Wohlfahrt-Veje et al, 2009).
The dimorphism of the relative susceptibility to sex reversal between sexes (the much greater frequency of morphological reprogramming in ovaries than in testes) is possibly related to the presence or absence of stem cells in the corresponding adult cell lineages. Indeed, it is well known that stem cells exist among pregranulosa cells, which retain the ability to replicate throughout life, but stem cells are not found among adult Sertoli cells (Kossowska-Tomaszczuk et al, 2009). There are thus provocative findings that link Foxl2 and stem cell–ness of gonadal somatic cells, with clear implications for female reproduction. Nevertheless, all results on Foxl2 thus far were obtained in animal models, and it is not possible to predict whether they will apply to humans. For example, following our work in mice, a sharp dichotomy in expression pattern between FOXL2 and SOX9 was documented in humans as well (Hersmus et al, 2008), but it remains to be seen whether any mutations involving FOXL2 can lead to 46,XX sex reversal in patients.
Sex Commitment and Reversal in Lineages in Mice vs Higher Mammals
Ablation of single genes involved in gonadal sex determination has
apparently far more penetrant effects in higher mammals than in rodents in the
3 cases studied thus far. For Rspo1, its absence leads to nearly
complete sex reversal in humans (Parma et
al, 2006), rather than the partial reversal in mice
(Chassot et al, 2008;
Tomizuka et al, 2008). A case
of 46,XX maleness associated with a mutation in WNT4 has now
unequivocally been reported in humans
(Mandel et al, 2008), which
again contrasts with the much milder mouse phenotype
(Vainio et al, 1999). And for
Foxl2, the partial sex reversal in the mouse knockout
(Ottolenghi et al, 2005)
contrasts with the sometimes nearly complete phenotypic sex reversal that is
observed when Foxl2 transcription is blocked by a naturally occurring
deletion in goats (Pailhoux et al,
2001).
Sex reversal becomes histologically complete, however, in the case wherein both Foxl2 and Wnt4 are ablated (Ottolenghi et al, 2007a). Figure 5 illustrates the subtle partial effect in newborn Wnt4–/– mice if even one Foxl2 allele remains active, and the overt resultant ovotestis that forms when both genes are completely gone. Laminin 1 immunostaining delineates structural features; the molecular indicator of sex reversal is the SOX9 protein, whereas a marker consistent with both primary and secondary sex reversal is a much earlier expression of anti-Müllerian hormone in the XX gonad (Figure 5A and B) than seen in newborn ovaries (Figure 5C). The Wnt4–/–;Foxl2–/– double knockout is the only instance that has been extensively explored; but the sum of current data suggests that compound knockout of several lineage-specific "master genes" is required for complete sex reversal in the murine model. However, even in this double-knockout model, as noted above, sex reversal is not as pronounced and does not occur as early as in transgenic mice expressing Sry or Sox9 (see also next section).
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In any case, because sex reversal in mice requires combined inactivations of genes that are individually able to produce sex reversal when they are ablated in higher mammals, it is conceivable that female sex–determining pathways may be more integrated and interdependent in higher mammals than in mice. In particular, one needs to reconcile the observation that the antitestis action of the same gene (Foxl2) that operates like an upstream regulator of female sex in goats (complete sex reversal phenotype in polled intersex syndrome goats lacking Foxl2 expression) is not at the top of a hierarchy in mice, and can be replaced by at least 1 other gene pathway (Rspo1; Chassot et al, 2008). This suggests that the PIS condition in goats may result from self-aggravating feedback interactions that would connect early ovarian genes. These interactions would be missing or would occur at later time points in mice, but would be facilitated if multiple lineage pathways are affected, as in the Wnt4–/–;Foxl2–/– animals.
This hypothesis may help to resolve another apparent contradiction between observations that are otherwise equally well founded. On the one hand, several unrelated ovarian genes are redundantly involved in antagonizing male sex determination in mice (see preceding) and likely in goats as well (in which RSPO1 and FOXL2 are expressed in partly distinct cell populations; Kocer et al, 2008). On the other hand, long-standing genetic evidence, from recessive cases of XX sex reversal in humans and goats, indicates that single loci can apparently alter the entire mechanism of engagement of the bipotential gonad into female sex determination (McElreavey et al, 1993). In addition, mutations associated with XY sex reversal may be interpreted as indicating primary antitestis effects by a single ovarian gene in mice—although alternative interpretations are possible (Eicher and Washburn, 1986). Thus, the autonomy of distinct ovarian pathways is still consistent with primary XX sex reversal–like phenotypes in higher mammals, and could extend to mice without involving any additional upstream regulator. It would rather involve some alteration of regulatory connections among the known ovarian genes or other ovarian genes operating at the same level of the hierarchy.
Similar feedback interactions may regulate male sex–determining genes downstream of Sry. They could account for the effects of single-gene mutations that all can lead to complete sex reversal when many other male sex genes are normal.
Alternative mechanisms to account for complete sex reversal cannot be excluded, but we suggest that regulatory interactions (eg, involving DNA targets of relevant transcription factors) are best suited to account for the fast evolutionary divergence that is observed across mammals. Overall, although certain mutations in some mammalian species simulate the effect of a single master regulator of female sex, there is no obvious need, nor any conclusive evidence, for such a single gene.
The Importance of Timing in the Race for Determination of Somatic Sex Commitment
We have suggested an updated version of classical models for gonadal sex
determination (Figure 3), in
which Sry/Sox9 have a head start in the bipotential gonad if
they are present. If they are not, Foxl2, Rspo1/Wnt4, and
other female genes are derepressed and turn on further ovary development. To
account for the reactivation of the testis pathway if Foxl2 or other
ovarian genes are absent in XX individuals, we have followed and modified the
traditional suggestion that the process of stroma mobilization at the time of
follicle formation may be homologous to testis tubule formation, and may thus
predispose the ovary to sex reversal
(Ottolenghi et al, 2007b). As
for the arguments favoring this notion, we have recently used genome-wide
expression profiling to provide molecular evidence for a differential timing
of activation of malelike genes in testes (early) vs ovaries (late) that is
the inverse of the timing of entry into meiosis
(Garcia-Ortiz et al, 2009).
But perhaps the most striking recent argument for similarity between early
testis and peri-postnatal ovary development is provided by the association of
mutations involving steroidogenic factor 1 (SF1/NR5A1) both with premature
ovarian failure in 46,XX individuals and with complete sex reversal in 46,XY
individuals (Laurenço et al,
2009). Thus, a gene long known to be associated with early testis
differentiation also affects later events of ovary differentiation or
maturation in humans.
Mechanistically, at least some testis genes (including SF1/NR5A1) are thus activated to support follicle formation or later features of folliculogenesis in the ovary; but during normal ovary development, the function of these genes is apparently confined within limits compatible with ovary development. If the safeguard mechanism fails, the male pathway can be derepressed in full, notably including the expression of male-specific Sox9, and sex reversal ensues.
An unresolved critical question is whether there are multiple sequential malelike activities antagonized by distinct ovarian genes in female gonads, or whether there is a single malelike pathway that is activated more or less late during development in different species (or under different conditions) and is antagonized by a single female mechanism. The former possibility is more or less implicit in most current models, whereas the latter was termed the M hypothesis (Ottolenghi et al, 2005, 2007a,b).
The M hypothesis implies that depending on context, and notably in available mouse models, malelike genes can start to be expressed so late that they only produce partial secondary sex reversal in XX gonads lacking female-determining genes. By contrast, in higher mammals, malelike genes are clearly able to produce earlier forms of complete or nearly complete sex reversal (See "Sex Commitment and Reversal in Lineages in Mice vs. Higher Mammals"). The M hypothesis also requires that female genes be expressed throughout female reproductive life, that is, as long as folliculogenesis and other testis formation–like processes such as stroma mobilization continue. Genes expressed both before and after birth, such as Foxl2, are the best candidates for such an action, although other genes are clearly involved before birth (Rspo1 and Wnt4) or after birth (aromatase, estrogen receptors, and others). In this framework, lifelong expression of FOXL2, as well as its involvement in premature ovarian failure in women, suggests that the mechanisms of maintenance of female sex determination may participate in the mechanisms that regulate menopause (Ottolenghi et al, 2005).
Alternatively, it is possible that one or multiple distinct malelike activities as well as additional female-determining genes may act before Rspo1, Wnt4, and Foxl2 (again corresponding to question marks in Figure 1). However, this possibility would not explain why in humans, the phenotypes of 46,XX sex-reversed patients that harbor mutations in Rspo1 or in other putative ovarian genes are more clearly primary than is observed in mice, but they are systematically less pronounced than is seen when Sry or Sox9 has directly been activated in XX individuals (by natural chromosomal rearrangements or transgenic constructs; Sinclair et al, 1990; Koopman et al, 1991; Bishop et al, 2000; Vidal et al, 2001).
What can we infer from these results about the mechanisms of sex determination, that is, the antagonistic gene interactions underlying the sex fate choices? In male embryos, it seems reasonable that Sry would induce the active suppression of femalelike genes such as meiotic genes, as well as the activation of malelike genes such as SF1/NR5A1; but, in females, can the transient embryonic suppression of malelike genes be the effect of female sex determination pathways? Any such mechanism would confer a risk that such early-acting, default female sex–determining genes might interfere with Sry in XY individuals. Thus, it is reasonable to suggest that other, sex-nonspecific processes (acting in the bipotential gonad) keep malelike genes from early expression in all individuals, as this would be particularly important in prospective females. Malelike gene expression would also be repressed by (other?) bipotential gonad genes, and it would be released in females at late time points when definitive female sex–determining genes are already active. This was in fact the M gene hypothesis (cf Figure 3), stating that M (malelike) activity in females follows an "Od/Z" (female-determining activity), which itself follows Sry (Ottolenghi et al, 2005).
A prediction of the M gene hypothesis is that female-to-male sex reversal due to the loss of female genes would always occur later than female-to-male sex reversal associated with gain of male gene activity. Also, the inferred later timing of activation of malelike genes, coupled to the fact that several autonomous antitestis pathways appear to be involved in female sex determination, would imply that sex reversal may be less complete following the loss of female genes than by gain of malelike activity. This is consistent with all available observations (see preceding).
We have suggested that the yin and yang of sex determination may involve direct competition between Foxl2 and Sox9. It is a close race, because Foxl2 begins to be expressed in female bipotential gonad within 24 hours of the initiation of Sox9 in the male, and in mice lacking Foxl2, testis markers are already sharply activated by E13 (and more sharply activated if Wnt4 is also ablated; data not shown). Furthermore, in XY ovotestes obtained either in natural mouse mutants or in transgenic mice, a slow-motion version of the sex determination race is apparent: somatic cells expressing Sox9 or Foxl2, but not both, appear to push toward alternative states while they stay intermingled for a relatively long period of time (Ottolenghi et al, 2007a; Wilhelm et al, 2009).
In particular, the implication that testis genes remain accessible to transcription in ovaries and can thus be expressed in the absence of Foxl2 is paralleled in experiments in which a Foxl2 transgene under a controllable heat shock promoter was activated at E15 (Ottolenghi et al, 2007a). When activated in the testis, the transgene was able to inhibit the transcription of most testis marker genes and induce a series of ovary markers to expression levels comparable to those in the ovary. Furthermore, when the transgene was activated in the ovary, it augmented the synthesis of many ovary markers about 2-fold! Markers included germ cell as well as somatic cell genes (Ottolenghi et al, 2007a; Garcia-Ortiz et al, 2009). Thus, "sex-determined" gonads seem to remain primed to turn on opposite sexually dimorphic genes and pathways if the right master transcription factors are active.
Notably, a very similar mechanism to that discussed here for somatic sex determination is also topical for germ cell sex determination, with a race envisaged between male and female factors—though those factors are incompletely identified (Kocer et al, 2009).
Open Questions for the Next Phase of Investigations
The current level of information offers a glimpse of the overall course of
gonadal differentiation and the genes involved in sex determination and the
maintenance of reproductive capacity. However, no one would deny that the
knowledge of the increasing cast of gene characters in this lifelong drama far
exceeds our knowledge of the plot. Here are some open questions for the coming
phase of studies.
Acknowledgments
We thank Chris Ottolenghi (Université Paris Descartes, Paris, France) for insightful suggestions and for the immunochemistry.
Footnotes
Supported by the Intramural Research Program of the National Institute on Aging, NIH.
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