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BOR - Papers in Press, published online ahead of print December 7, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.047134
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BIOLOGY OF REPRODUCTION 74, 450–458 (2006)
DOI: 10.1095/biolreprod.105.047134
© 2006 by the Society for the Study of Reproduction, Inc.

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Contribution of Germ Cells to the Differentiation and Maturation of the Ovary: Insights from Models of Germ Cell Depletion

Celine J. Guigon , and Solange Magre 1 

Laboratoire de Physiologie et Physiopathologie, CNRS-UMR 7079, University Pierre et Marie Curie, 75005 Paris, France


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 
In mammals, the role played by germ cells in ovarian differentiation and folliculogenesis has been the focus of an increasing number of studies over the last decades. From these studies, it has emerged that bidirectional communication between germ cells and surrounding companion cells is required as soon as the initial assembly of follicles. Models of germ cell depletion that arise from both spontaneous and experimentally induced mutations as well as irradiation or chemical treatments have been helpful in deciphering the role played by germ cells from the onset of ovarian differentiation onward. This review reports current knowledge and proposes novel hypotheses that can be formulated from these models about the contribution of germ cells to ovarian differentiation and folliculogenesis. In particular, it promotes the idea that the influence of germ cells on companion somatic cells varies within both ovarian differentiation and folliculogenesis.

developmental biology, follicle, gamete biology, granulosa cell lineage, granulosa cells, oocyte, oogonia, ovary, Sertoli-like cells, transdifferentiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 
Female fertility depends on the supply and maturation of the ovarian germ cells, i.e., the oocytes, and the differentiation and proliferation of the ovarian somatic cells, i.e., granulosa and thecal cells. Assembly of oocytes and somatic cells into follicular structures, a process also called initial folliculogenesis or follicle histogenesis, marks the last step of ovarian differentiation and occurs during fetal life in humans and within the first week of postnatal life in rodents (for review, see [1]). During folliculogenesis, oocytes grow surrounded by an increasing number of granulosa cell layers and, from the preantral stage onward, thecal cells differentiate outside the follicle. Improper ovarian differentiation or folliculogenesis due to intra- or extraovarian regulation defects often results in premature ovarian failure, leading to infertility.

Although oocytes had long been considered as merely ensuring the propagation of species through fertilization, recent studies have enlightened their active role during folliculogenesis in regulating the growth and maturation of their companion granulosa cells (for review, see [2, 3]). Prior to folliculogenesis, during ovarian differentiation, there is evidence that germ cells also play an important role. Indeed, in their absence, the differentiation of the ovary is affected and no follicles form [4]. This is in marked contrast with what is observed in males, where germ cells are not necessary for the differentiation of seminiferous cords, although possibly reinforcing testis differentiation [5, 6]. If the complete loss of germ cells inevitably leads to sterility, models of germ cell depletion in females indicate that the developmental or follicular stage at which germ cells are lost influences subsequent differentiation and maturation of the ovary or the follicle. Dissecting the ovarian or follicular phenotype of these different models may provide tools to better understand the involvement of germ cells in ovarian differentiation and their contribution to folliculogenesis. In this review, in summarizing observations performed on several models of germ cell depletion over the last decades, we report current opinions and propose novel hypotheses about the role of germ cells in the differentiation and maturation of the ovary, with special emphasis on the differentiation of the granulosa cell lineage. For the sake of clarity, an overview of current knowledge concerning normal ovarian differentiation and folliculogenesis in mammals is included.


   OVERVIEW OF OVARIAN DIFFERENTIATION
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 
From the Blastema

In both sexes, the undifferentiated gonads arise as thickenings of the coelomic epithelium on the ventrolateral surface of each mesonephros (a chronology of ovarian differentiation is provided for mice, rats, sheep, and humans in Table 1). Primordial germ cells (PGCs) migrate from outside the embryo through different tissues before colonizing the early gonads (or genital ridges) [7]. The proliferation of both germ cells and somatic cells leads to the rapid enlargement of the genital ridges. In the developing ovary, germ cells (or oogonia) and epithelial (pregranulosa) cells progressively organize into epithelial structures, called ovigerous cords (OCs), continuous with the surface epithelium of the ovary [8–14]. They are delimited by a thin basement membrane (BM) and bordered outside by mesenchymal cells (Figs. 1 and 2A). The differentiating ovary is, thus, organized into two distinct compartments from an early stage on: OCs and the interstitial tissue. Within OCs, oogonia enter prophase of the first meiotic division. The commitment into meiosis was proposed to occur cell autonomously and according to an intrinsic clock [15, 16]. The existence of specific somatic signal(s) regulating this event is, however, under discussion [17].


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  		TABLE 1. Principal steps of ovarian differentiation in the mouse, rat, sheep, and human.a


Figure 1
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  		FIG. 1. Ovigerous cords in the differentiating rat ovary at 15.5 days postconception. A) Immunodetection of laminin underlining the thin basement membrane of ovigerous cords. B) Electron micrograph of a portion of an ovigerous cord, showing germ cells (GC) and pregranulosa cells (PC). Outside the ovigerous cords, the interstitial tissue is composed of elongated mesenchymal cells (MC). Bar = 50 µm. Original magnification in B x2600


Figure 2
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  		FIG. 2. Diagram depicting the different steps of ovarian differentiation. A) In the first steps of ovarian differentiation, the ovigerous cords (OC), which are composed of germ cells (GC) and pregranulosa cells (PC) delimited by a basement membrane (BM), differentiate progressively. OCs are in continuity with the ovarian surface epithelium (OSE). Mesenchymal cells (MC) are located outside OCs in the interstitial tissue. B) During OC breakdown, PCs progressively rearrange around GCs, the pre-existing BM is destroyed, and a new one is synthesized (dotted lines). GCs have entered meiotic prophase and a number of them are apoptotic (black colored). C) OC breakdown leads eventually to the formation of primordial follicles (Pal foll.), constituted by a single GC in meiotic prophase surrounded by a layer of flattened granulosa cells (GrC), delimited by a continuous BM and bordered outside by MCs. See references in the text

to Follicles

During fetal development in domestic mammals and humans, and around birth in rodents, OCs breakdown progressively into follicular units comprised of a solitary oocyte arrested at the diplotene stage of meiotic prophase that is surrounded by a monolayer of granulosa cells delimited by a continuous BM (Fig.2, B and C). This process, involving the remodeling of the BM from OCs, may require the cooperation between pregranulosa cells, mesenchymal cells, and oocytes for the synthesis of proteinases inducing BM degradation [18]. The fragmentation of OCs into follicles follows a centrifugal pattern within the ovary [10, 13, 19]; in rats, it gives rise to two categories of follicles, primordial follicles located in the periphery and primary follicles located in the core of the ovary [19, 20]. Primary follicles grow rapidly in the days following their formation and constitute the initial waves of growing follicles that ensure the first ovulations of reproductive life [1, 21].

Massive Constitutive Germ Cell Death

During meiosis progression and follicle formation, many germ cells are eliminated (around 70% in mice, rats, and humans) [22–25]. The reason underlying constitutive germ cell death remains poorly understood, but it may well lead to the elimination of germ cells exhibiting defective nuclear or mitochondrial genomes [26, 27]. On the other hand, dying oocytes may play the role of nurse cells by transferring organites, such as mitochondria, to the surviving oocytes through intercellular bridges [24]. Moreover, oocyte death could possibly permit the association of appropriate numbers of pregranulosa cells around surviving germ cells for follicular formation [10, 18, 28]. The constitutive elimination of germ cells during ovarian differentiation may, thus, be a critical process, which could, intriguingly, favor reproductive success. Tight control of the balance between germ cell survival and death is, however, critical in preventing excessive germ cell death leading to ovarian dysgenesis and premature ovarian failure. The various models of ovarian dysgenesis induced by germ cell depletion during ovarian differentiation discussed in the following section are listed in Table 2.


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  		TABLE 2. Female germ cell loss during ovarian differentiation and ovarian phenotype


   WHAT CAN WE LEARN ABOUT THE CONTRIBUTION OF GERM CELLS TO OVARIAN DIFFERENTIATION FROM MODELS OF GERM CELL-DEPLETED OVARIES
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 
Germ Cells Contribute to Follicle Histogenesis

In the cases in which oogonia are absent or scarce within genital ridges, undifferentiated gonadal somatic cells still proliferate and the two ovarian compartments formed by OCs and interstitial tissue appear to differentiate similarly to normal ovaries [9, 29]. Nevertheless, germ cell-depleted OCs never break down into follicular units and may persist from weeks to months after birth in the ovary before regressing [9, 29–32]. Moreover, within germ cell-depleted OCs, epithelial cells retain molecular characteristics of pregranulosa cells [32]. Altogether, these observations suggest that, while germ cells may well play a key role in the morphogenetic events underlying follicle histogenesis, they would be involved in neither the initial growth of the undifferentiated gonad nor the differentiation of OCs. Whether these observations performed exclusively in rodents can be extended to other mammalian species remains to be determined.

There is little information on oocyte factors regulating follicle histogenesis. In recent years, genetic manipulations have permitted the identification of a germ cell-specific gene potentially involved in follicular histogenesis, i.e., factor in the germline alpha (Figla) which encodes a basic helix-loop-helix transcription factor [33]. FIGLA is expressed in germ cells as early as 13 day postconception in mice and by midgestation in humans [34, 35]. Mice deficient for Figla exhibit alterations in ovarian differentiation, as shown by the failure of OCs to break down into follicles and the massive oocyte death in the very first days following birth [34]. FIGLA could, thus, regulate follicle histogenesis. One cannot rule out, however, that it is indirectly involved in this process by merely regulating the survival of oocytes at the time of follicle histogenesis [34, 35]. Another oocyte-specific factor, called OG2 homeobox ([OG2X], also known as newborn ovary homeobox encoding gene or NOBOX) might also be involved in the regulation of follicle histogenesis, as mice deficient for Og2x show a marked delay in the process of ovigerous cord breakdown associated with a dramatic increase in oocyte death in the days following birth [36].

Germ Cells Are Potentially Involved in the Maintenance of the Ovarian Phenotype

The hypothesis that germ cells play a key role in the maintenance of the ovarian phenotype has arisen from observations reporting that ovarian sex reversal, i.e., the presence within the ovary of epithelial cords composed of cells displaying an elongated cytoplasm and a basally located nucleus and thus resembling Sertoli cells (classically referred to as Sertoli-like cells and the epithelial cords as seminiferous-like cords [SLCs]), is preceded by a massive loss of germ cells [4, 37]. Ovarian sex reversal was first shown to occur naturally in female cattle, or freemartin cattle (Fig. 3A), which share vascular connections with their male cotwins and are exposed in utero to the testicular hormones AMH (anti-Mullerian hormone, belonging to the transforming growth factor beta [TGFB] superfamily) and testosterone [38–40]. The gonads of freemartin cattle, before displaying SLCs, exhibit a markedly altered development, as shown by the early arrest of both gonadal growth and germ cell proliferation, the delayed commitment of germ cells into meiosis, and the progressive degeneration of oocytes. Similarly, in experimental models of ovarian sex reversal (Table 2), the development of SLCs is preceded by the loss of meiotic germ cells [41–49]. It is worth noting that, in these models, SLCs express AMH (Fig. 3B), which is normally present in Sertoli cells of the differentiating testis and absent in the ovary before follicular growth, a result that may confirm the transdifferentiation of cells from the granulosa cell lineage into Sertoli-like cells [41–43, 48, 50, 51]. In agreement with this result, further studies in one of these models (mouse fetal ovarian grafts), have shown the presence of specific junctional complexes of Sertoli cells, i.e., ectoplasmic specializations, between cells in SLCs [44, 45] in addition to the expression of the testis-specific gene Sox9 (SRY-box containing gene 9) [52].


Figure 3
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  		FIG. 3. Presence of seminiferous-like cords (SLC) within fetal freemartin bovine gonads. A) Histological section of a gonad at 97 days postconception. Note the presence of an oocyte (arrow) within the SLC. B) Immunohistochemical detection of AMH at 135 days postconception. The presence of AMH is detected in cells of SLCs (arrowheads). Bars = 20 µm (A) and 60 µm (B). Photos generously provided by Dr. Vigier

The presence of structures resembling seminiferous cords has been reported rarely in the case of germ cells being lost at the mitotic stage ([53], and see discussion in [54]). It can be assumed, as previously suggested [4], that the loss of germ cells at the meiotic rather than the mitotic stage may lead to the transdifferentiation of the granulosa cell lineage (Table 2). Recent experimental studies, using reassociation of male gonadal somatic cells and female germ cells, have shown that oocytes, and not oogonia, could inhibit differentiation of seminiferous cords in males [55]. These studies suggest indirectly that oocytes, and not oogonia, may play a key role in the maintenance of the ovarian phenotype by antagonizing the testis differentiation pathway [55]. It is intriguing, however, that ovaries that have never contained oocytes due to early germ cell loss display sterile OCs and fail to develop SLCs [29, 31, 32]. This may indicate that cells of the granulosa cell lineage can transdifferentiate into their testis counterparts only after having reached a certain maturation status, which depends on the presence of meiotic germ cells. These data suggest that, during ovarian differentiation, germ cells committed into meiosis on the one hand inhibit the male differentiating pathway and on the other hand promote the maturation of ovarian somatic cells so that they can possibly transdifferentiate into Sertoli-like cells.

Meiotic germ cell loss during ovarian differentiation is, however, not necessarily followed by ovarian sex reversal. In mice deficient for the Dazl gene (deleted in azoospermia-like, a member of the DAZ/SPGY family), germ cells are lost in early meiosis stages. After careful examination of the ovaries in fetal and postnatal life, no SLCs are reported [56, 57]. Additionally, in mouse deficient for Figla (see above), germ cell loss occurs around the time of follicle histogenesis, and the ovaries exhibit sterile OCs (Table 2). Although these models may challenge the current hypothesis on the role of meiotic germ cells in the maintenance of the ovarian phenotype, they may also suggest that germ cell loss is not sufficient in itself to permit the transdifferentiation of the granulosa cell lineage. It is worth noting that, in the in vivo models of ovarian sex reversal (see Table 2, freemartin cattle, mouse fetal ovarian grafts, transgenic mice overexpressing Amh and Wnt4 deficient mice), SLCs appear around the time of follicle formation, suggesting that cells of the granulosa cell lineage must reach a certain maturation state before converting into Sertoli-like cells ([45], and see below). As the genes Dazl and Figla are both expressed early during ovarian differentiation [34, 56], it is possible that, in their absence, ovarian somatic cells do not mature sufficiently to acquire the capacity for converting into Sertoli-like cells.


   OVERVIEW OF OVARIAN FOLLICULOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 
Follicular Growth and Atresia

Regularly and until exhaustion, primordial follicles or resting follicles are recruited into the growing follicle pool. When a primordial follicle enters growth, its surrounding granulosa cells, initially flattened, become cuboidal and proliferative. Follicles reach the primary, preantral, and antral stages (for follicle classification, see [58, 59]) and from puberty onward, it can pass into the preovulatory follicle stage in which the oocyte resumes meiosis and becomes arrested again in metaphase II. The oocyte is then ovulated in the oviduct, ready for fertilization. Subsequently, theca and granulosa cells differentiate into luteal cells and form the corpora lutea, which produces progesterone.

Throughout the ovarian lifespan, a dramatic number of follicles is eliminated by the process of follicular atresia (for review, see [60]). During this process, oocytes and granulosa cells degenerate while thecal cells persist, becoming hypertrophied and subsequently forming interstitial glands that display steroidogenic capacities. Although recent studies have supported the fact that female germ cell renewal occurs after birth in mice [61, 62] and possibly in humans [63], the progressive decline in follicle number leads inevitably to the arrest of the reproductive function.

Regulatory Mechanisms Involved in Folliculogenesis

The proper production at each cycle of fertilizable ova involves tight interaction between the hypothalamo-pituitary axis and the ovary through regulatory loops mediated by endocrine factors. Although the growth of primary and preantral follicles can take place in the absence of gonadotropins, these follicles may be responsive to gonadotropins [64, 65]. Optimal development of preantral follicles may, thus, require these hormones. In contrast, development beyond the antral follicle stage is clearly dependent on gonadotropins for growth, maturation, and survival of follicles [59, 60]. Paracrine factors and intercellular gap junctions ensure complex bidirectional communication between the oocyte and its surrounding somatic cells during folliculogenesis, for the coordinated development of both somatic cell and germ cell compartments [2, 3, 66]. In this dialogue, the oocyte plays a key role from early stages of follicular growth on [67].


   WHAT CAN WE LEARN ABOUT THE CONTRIBUTION OF THE OOCYTE TO FOLLICULOGENESIS FROM IN VIVO AND IN VITRO MODELS OF OOCYTE-DEPLETED FOLLICLES
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
CONCLUSIONS
 REFERENCES
 
The Oocyte Stimulates Granulosa Cell Proliferation

In vitro studies have shown that growing oocytes promote proliferation of granulosa cells from both preantral and antral follicles, as the microsurgical removal of the oocyte (or oocytectomy) from these follicles induces a decrease in granulosa cell proliferation and the addition of medium conditioned by oocytes restores proliferation [68]. Taking advantage of a rat experimental model in which oocytes from resting follicles are depleted following {gamma}-irradiation in neonatal life, we have shown that granulosa cells of oocyte-depleted (OD) follicles survive and retain proliferative capacity [21, 69]. The proliferative capacity of granulosa cells of OD resting follicles reaches very low levels, however, compared with that of normal resting follicles (4.5% ± 0.9% of OD resting follicles with at least one BrdU-positive granulosa cell in prepubertal irradiated ovaries versus 21.4% ± 2% of normal resting follicles in control ovaries; n = 4 ovaries in each group; Student t-test, P < 0.01; unpublished data), a result underlying the fact that the oocyte exerts a potent mitogenic effect on its companion somatic cells as soon as the resting follicle stage.

Among the oocyte-specific factors potentially involved in granulosa cell proliferation, two members of the TGFB superfamily have been identified, namely growth differentiation factor (GDF) 9 and bone morphogenetic protein (BMP) 15. In mice deficient for Gdf9, follicular growth is blocked at the large primary stage due to the arrest of granulosa cell proliferation; the oocyte, however, continues to grow and eventually degenerates [70, 71]. A similar ovarian phenotype has been observed in ewes carrying a point mutation in BMP15 (Inverdale ewes) [72–74]. Subsequent studies have confirmed that both factors can stimulate the progression of folliculogenesis from the primary stage onward [75–79]. Oocyte factors potentially involved in the initiation of follicular growth include the receptor KIT, activated through signaling by KIT ligand from granulosa cells, as well as fibroblast growth factor 2 [80–84].

The Oocyte Is Involved in Granulosa Cell Differentiation

Evidence that the oocyte may influence the differentiation status of granulosa cells was first provided by Nalbandov laboratory, which showed that the oocytectomy of rabbit preovulatory follicles in vivo leads to the early luteinization of the follicles (Table 3) and increased progesterone production [85]. Similarly, granulosa cells from rat antral follicles transform into luteal cells after oocytectomy (Table 3), a process that does not occur if oocytectomized antral follicles are cocultured with oocytes [86]. These studies proposed that the oocyte may well secrete a factor preventing the luteinization of follicular cells, but this factor remains to be identified.


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  		TABLE 3. Oocyte loss and follicle phenotype

Subsequent experiments have shown that the oocyte contributes substantially to the differentiation of its surrounding granulosa cells throughout folliculogenesis. The oocyte regulates the steroidogenesis of granulosa cells, for example, in inhibiting progesterone production, as early as the preantral follicle stage [87–89]. In addition, within the large antral follicle, the oocyte plays a role in the establishment of the heterogeneous functionality of the two granulosa cell subpopulations, i.e., mural granulosa cells and cumulus cells. After gonadotropin stimulation, mural granulosa cells express the receptor for the gonadotropin hormone LH (Lhcgr), according to a gradient decreasing toward the oocyte [90–92], while cumulus cells synthesize hyaluronic acid, an extracellular matrix component enabling the expansion of the cumulus within the follicular cavity [93]. In vitro, the expression in granulosa cells of Lhcgr was suppressed and that of hyaluronic acid was stimulated by the oocyte [94–96]. From these studies, it has been proposed that, in the absence of the oocyte, gonadotropins and other factors may drive granulosa cell differentiation toward the mural phenotype and luteinization. The acquisition of the mural phenotype would be the default pathway of granulosa cell differentiation, a pathway that could be prevented by oocytes [2].

In follicles at earlier stages that are unresponsive or weakly responsive to gonadotropins, how do granulosa cells differentiate in the absence of the oocyte? Some information can be gleaned from experimental in vivo models. Studies carried out on the ovaries of neonatal irradiated rats containing OD resting follicles or on Inverdale ewes and Gdf9 null mice, which both exhibit OD primary follicles, have shown that granulosa cells survive and progress in their maturation (Table 3) [69, 71, 97]. Indeed, in OD resting follicles, granulosa cells acquire molecular characteristics of granulosa cells from primary follicles, as they express, for example, AMH [69]. In OD primary follicles, granulosa cells acquire molecular characteristics of granulosa cells from preantral follicles in Inverdale ewes and a luteal-like phenotype in Gdf9 null mice [71, 97]. The discrepancy in the granulosa cell fate following oocyte loss between these two models may well be explained by the fact that, in Gdf9 null mice, there is a decoupling at the time of oocyte loss between the morphological aspect of the follicle, considered at the primary stage, and the functionality of its granulosa cells, displaying markers of those in preantral follicles [71]. After oocyte loss, granulosa cells exhibit characteristics of granulosa cells from antral follicles before exhibiting characteristics of luteal cells [71]. Thus, whereas granulosa cells survive and pursue their maturation in the absence of the oocyte, they may terminate their differentiation into luteal cells only if they have reached a sufficient status of maturation by the time of oocyte loss. This maturation status, according to the different models reported here, would not be reached before the preantral stage. From these studies, one may hypothesize that the maturation of granulosa cells in early follicles is either cell-autonomously driven or involves paracrine and endocrine factors. On the other hand, one cannot rule out that alternative molecular pathways may be activated in granulosa cells of OD follicles, compensating for the absence of the oocyte.

The Oocyte Is Involved in the Maintenance of the Morphological Phenotype of Granulosa Cells

In our study of neonatal irradiated ovaries, we found that granulosa cells from OD resting follicles displayed important morphological alterations, as they eventually resembled Sertoli cells. They displayed a marked cytoplasmic expansion, a basally located nucleus (Fig. 4), and ectoplasmic specializations, which are normally present exclusively in Sertoli cells [69]. However, these cells retained the expression of the granulosa cell-specific factor forkhead box L2, and did not express the testis-specific factor SOX9, in contrast with the Sertoli-like cells observed in sex-reversed mouse fetal ovarian grafts [52, 69]. The reasons underlying this discrepancy are presently unknown. It can be assumed, however, that pregranulosa cells in fetal ovaries retain a high capacity to transdifferentiate into Sertoli-like cells, whereas granulosa cells in primordial follicles have lost partially such capacity.


Figure 4
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  		FIG. 4. Morphological alterations of granulosa cells from resting follicles following oocyte loss. A and B) Histological sections of neonatally irradiated ovaries at 4 (A) and 12 (B) wk. Oocyte-depleted resting follicles (arrowheads) are composed of granulosa cells delimited by a continuous basement membrane. As animals age, cells within oocyte-depleted follicles (arrows) exhibit profound morphological alterations, as illustrated by the marked cytoplasmic expansion and the basally located nucleus. Bars = 30 µm

Altogether, our observations have demonstrated that, within resting follicles, the oocyte is engaged in the maintenance of the granulosa cell lineage phenotype. However, the morphological transdifferentiation process requires a preliminary maturation of granulosa cells to a primary-like follicular stage and, possibly, the action of the endocrine environment through an FSH-mediated pathway [69]. Therefore, in OD resting follicles, oocyte loss together with intra- and/or extraovarian factors may well contribute to the transdifferentiation of granulosa cells.

From the results obtained in mice deficient in both types of functional estrogen receptors, ESR1 (also known as estrogen receptor alpha) and ESR2 (also known as estrogen receptor beta), as well as in females incapable of synthesizing estrogens due to disruption of the Cyp19a1 gene encoding the P450-aromatase enzyme, there is some evidence that estrogen signaling plays a key role in the maintenance of the granulosa cell phenotype [98–100]. The differentiation of cells resembling Sertoli cells have been observed in the ovaries of adult mice overexpressing or lacking the gene follistatin [101, 102], in some types of ovarian tumors in women [103], and in ovarian tumors from mice deficient for the inhibin alpha gene [104–108], but further morphological and molecular studies are required to better define these cells. Although it appears that, in these models, impaired extra- and intraovarian regulation is primarily involved in the conversion of granulosa cells into cells resembling Sertoli cells, the potential implication of oocyte defect or loss remains, however, to be investigated.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
REFERENCES
 
Overall, these studies lead us to propose a model for the contribution of germ cells to ovarian differentiation and folliculogenesis (Fig. 5). While germ cells would be unnecessary for the early differentiation of the ovary, i.e., for the formation of OCs and, thus, for the differentiation of pregranulosa cells, they are involved in follicle histogenesis and, either directly or indirectly, in the differentiation of pregranulosa cells into granulosa cells. During folliculogenesis, germ cells interact with their surrounding granulosa cells by stimulating their proliferation and differentiation and, in advanced follicular stages, by preventing their premature luteinization. Concerning the recruitment of thecal cells around growing follicles, there is some evidence that germ cells may also play a role, either directly, by the mean of paracrine factors, or indirectly by inducing the granulosa cells to produce a recruitment factor [71].


Figure 5
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  		FIG. 5. Hypothetical contribution of female germ cells to the differentiation and maturation of cells from the granulosa cell lineage from the initial steps of ovarian differentiation to the last stage of folliculogenesis. See text for explanations and references

There are several lines of evidence indicating that germ cells, particularly when they are in meiosis, may well prevent the conversion of cells from the granulosa cell lineage into Sertoli-like cells. As reported in this review, the development of SLCs following oocyte loss occurs in vivo around the time of follicle formation (freemartin cattle, mouse fetal ovarian grafts, transgenic mice overexpressing Amh, Wnt4-deficient mice) or in early stages of folliculogenesis (neonatal irradiated rats). These results lead to proposing the following hypothesis: after oocyte loss, cells from the granulosa cell lineage have the ability of acquiring characteristics of Sertoli cells when they have a relatively mature differentiation status as compared with those in OCs, or conversely, when they have a relatively immature differentiation status as compared with those in growing follicles (Fig. 5). The ability of cells from the granulosa cell lineage to switch into those from the Sertoli cell lineage probably reflects the developmental relationship between these two lineages because they would arise from the same gonadal precursors [109]. In males, however, there are, to our knowledge, no reports showing the transdifferentiation of Sertoli cells into granulosa cells, except in some cases of testicular tumors where granulosa-like cells are described [104]. These facts indicate the considerable plasticity of cells from the granulosa cell lineage, a property that may be related to their capacity of exhibiting marked morphological and molecular alterations during folliculogenesis and luteinization.

In females, the existence of an ovarian-determining gene is still under investigation [110, 111]. The complete understanding of the mechanisms of ovarian differentiation will require a more comprehensive knowledge of the complex and long-lasting morphogenetic processes leading to the edification of the ovary. Within this perspective, further insights into the interplays between germ cells and their somatic environment crucial to the differentiation and maturation of the ovary would seem indispensable.


   ACKNOWLEDGMENTS
 
This article is dedicated to Alfred Jost. The authors wish to thank Dr. B. Vigier for his kind gift of freemartin gonad illustrations. The authors also wish to thank Dr. S. Bouret and Mrs. M. Montagne for helpful advice on the manuscript.


   FOOTNOTES
 
1 Correspondence: Solange Magre, Laboratoire de Physiologie et Physiopathologie, CNRS-UMR 7079, University Pierre et Marie Curie, 7 Quai Saint Bernard, 75005 Paris, France. FAX: 33 1 44 27 26 50; solange.magre{at}snv.jussieu.fr Back

Received: 1 September 2005.

First decision: 23 September 2005.

Accepted: 1 December 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 OVERVIEW OF OVARIAN...
 WHAT CAN WE LEARN...
 CONCLUSIONS
 REFERENCES
 

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