Abstract
Most of our understanding on the origin, specification and development of the female germ line in placental mammals comes from studies in the laboratory mouse. The molecular pathway leading to the development and establishment of the female germ line in mouse has erected as the paradigm for placental mammals. It remains, however, largely unexplored whether the well-established mouse regulatory pathway is a common mechanism to other or all placental mammals. Discrete differences in mammals other than mouse reveal the existence of alternative mechanisms that challenge the currently accepted tenets on the origin and establishment of the mammalian female germinal reserve. Here, we will discuss the mouse framework in the light of emerging discrepancies seen in other placental mammals.
Keywords
- placental mammals
- primordial germ cells
- female germ line development
- germinal reserve
- ovarian development
1. Introduction
Germ cells are the only cell types capable of transmitting the genetic traits of an individual. They differentiate into spermatozoa and oocytes in adult testis and ovary, respectively, and give rise to a totipotent zygote after fertilization. Germ cells guarantee the perpetuation and diversification of the genetic information across the generations in most multicellular organisms. The developmental pathways that lead to the formation of a highly specialized germ cell are long and complicated, and the molecules that are involved in this process are still a matter of discussion. One extraordinary feature in the germ cell lineage in mammals is the fact that specification occurs far from the gonads, implying a necessary migratory phase after specification. A second feature is their unique capacity to undergo meiosis, in which chromosome recombination generates genetic variation in the haploid gametes [1, 2, 3, 4].
Most of our understanding regarding germ cell specification and differentiation in mammals comes from studies in the laboratory mouse. It is widely accepted that specification of primordial germ cells (PGCs) in mouse takes place at a very early stage in development; more precisely, they are thought to be set apart following blastocyst implantation in the proximal epiblast of the gastrulating embryo [2]. So far, however, no lineage tracing study has shown that those early segregated PGCs finally end up in the gonads [5]. Alternatively, it has been proposed that presumptive early specified PGCs in the proximal epiblast are rather a primordial pool of stem cells from which PGCs can be specified later on in development, probably during migration toward the emerging gonad [5]. Both explanations have been raised from mouse embryo studies. Nevertheless, there are some key embryological differences between the mouse and other mammals, especially at the epiblast stage when PGCs are specified. The epiblast of the murine rodent forms a cup-shaped egg cylinder, but most other mammals have a flat disk-like epiblast. Signals from extraembryonic tissues induce germ cell fate in a subset of epiblast cell at a specific position with optimal concentration and timing of signals. As PGC specification largely depends on signals from surrounding tissues, the morphology of the embryo is crucial for dissecting out the mechanisms of germ line establishment in different mammals since tissues surrounding the epiblast in the egg cylinder are not the same in flat-disk embryos [6].
2. The mouse model for primordial germ cell specification
2.1. The egg cylinder
In mouse, the blastocyst implants in the uterus by E4.5. The inner cell mass (ICM) of blastocyst is the source of epiblast cells. The ICM is segregated into epiblast and hypoblast or the primitive endoderm. Epiblast cells are equipotent and give rise to all the somatic and germ cells. During implantation, when the syncytiotrophoblast starts to penetrate the wall of the uterus, the epiblast and hypoblast are physically constrained and form a bilaminar embryo. The internal epiblast cells reorganize from a ball of cells into a cup-shaped epithelium surrounded by hypoblast. Immediately before gastrulation (E6.0 and E6.5), the mouse embryo can be visualized as a thick-walled cup of tissue (the epiblast or embryonic ectoderm), which gives rise to the entire fetus and some of the placental membranes. A second thick-walled cup of tissue (the extraembryonic ectoderm, ExE) placed overturned on the epiblast will give rise to the main part of the placenta. Both cups are enclosed in a thin bag of primitive endoderm-derived visceral endoderm (VE) [2, 7, 8].
The embryonic disk is forced into a complex shape called the ‘egg cylinder’ in which the anterior and posterior poles of the embryo come in close proximity to each other. Around E4.5 and E5.5, the ExE arises from the polar trophoectoderm (TE) and makes contact with the underlying epiblast. At E6.5, gastrulation starts with the formation of the primitive streak at the posterior region of the embryo. At E7.5, epiblast cells migrating first through this structure include the PGC precursors, which form the extraembryonic mesoderm [9, 10].
2.2. Mechanism for PGC specification
In mouse, PGCs originate from the most proximal epiblast cells by induction of the ExE and VE. Both extraembryonic tissues surround the epiblast cell of the postimplantation egg cylinder at around E5.0–E6.0. The ExE and VE release the bone morphogenetic protein (BMP) 4, 8b and 2 to instruct a small number of pluripotent proximal epiblast cells to become competent to be PGCs, suppressing a somatic program that is adopted by neighboring cells [11] (Figure 1).
Accordingly, BMP4 released from the ExE activates the expression of B-lymphocyte–induced maturation protein 1 (
Blimp1 protein signal first appears in about 6 cells in the most proximal epiblast at the posterior side of the embryo. Blimp1+ cells initially express the
Following lineage restriction, PGC precursors initiate germ cell specification by activating
Blimp+ PGC precursors proliferate and move into the extraembryonic mesoderm (ExM); they reexpress pluripotency-associated genes (
With the establishment of germ cell fate, germ cells express factors like alkaline phosphatase (AP), Nanos3, Dazl, mouse vasa homologue (Mvh) and Dnd1 [2]. They increase in number and move out of the embryo by the primitive streak in formation toward the extraembryonic mesoderm at the base of the allantois at E7.25. As mentioned above, PGCs form a cluster of cells 6 to 16 cells at around E6.5; then, they increase to approximately 20–28 cells, move posteriorly and develop into PGCs at E6.75-E7. During early gastrulation, the PGCs form a cluster of 40–50 cells at the base of the incipient allantois in the ExM at around E7.25 [33, 34]. Subsequently, and concomitant with an increase in their number, at around E8, they start to translocate one by one toward the developing hindgut endoderm and move through it. They then leave the endoderm to emerge in the mesentery and at around E10.5 colonize the embryonic gonads, where they proliferate and initiate a differentiation into either oocytes or spermatozoa depending on the embryo sex.
2.3. Migration of PGCs
PGCs in the mouse may be motile from their onset (E7.25) until they colonize the genital ridge (E11.5). After formation, PGCs move through the posterior primitive streak and invade the definitive endoderm and posterior extraembryonic structures. Following subsequent migration within the hindgut during its anterior extension (E8-E9.5), mouse PGCs migrate through the hindgut tissue to the mesoderm, followed by bilateral migration toward the gonadal ridges (E10.5–11.5). During this pregonadic phase, PGCs can be identified by morphological criteria and surface markers, such TNAP and SSEA-1, and the expression of pluripotent markers like Oct4, Sox2 or Nanog [35].
Six distinct stages of PGC behavior in the migratory process were identified, including: (i) invasion of the endoderm, (ii) passive or active migration into the hindgut, (iii) random migration within the hindgut, (iv) migration from the gut to the genital ridges, (v) clustering at the ridges and (vi) cell death within midline structures [36].
At E7.5, PGCs move through the primitive streak and into the definitive endoderm. Some PGCs also end up in the allantois and/or parietal endoderm. The fate of PGCs in extraembryonic structures remains uncertain, but PGCs in the definitive endoderm become incorporated into the hindgut, and at E9.0, they can be found moving within and around the cells of the hindgut epithelium [36]. At E8.5, PGCs on the lip of the hindgut pocket have a rounded nonmotile morphology suggesting that PGCs are passively incorporated into the gut and then, at stage (iii), they reinitiate active motility around the epithelial cells.
Interactions between PGCs may also be important for their homing behavior. PGCs emerge from the gut individually, but during migration, they interact with each other forming a migrating network of cells [37]. This network becomes progressively aggregated into clusters of cells toward the end of migration. Antibodies against E-cadherin blocked the process of PGC aggregation in cultured embryo slices and prevented PGCs from forming tight clusters at the genital ridges [38].
At the end of their migration, PGCs presumably lose their motile properties as they associate with somatic cells in the gonad and acquire sex-specific morphologies. There does not seem to be any evidence for sex-specific differences during germ cell migration.
2.4. An alternative hypothesis for PGC specification in mouse
The mouse pathway described above is the classical currently accepted model of PGC formation. This path establishes that PGCs originate and specify as an early lineage-restricted cluster of cells in the base of the allantois soon after implantation. Nevertheless, no definitive proof demonstrating the continuity of those presumptive early-specified PGC and the germ cells, which colonize the genital ridge, has so far been provided. In view of this, and critically reviewing the literature on PGC origin and specification in mouse, Mikedis and Downs [5] advocate in favor of an alternative hypothesis. These authors propose an alternative model in which the presumptive PGCs in the base of the allantois are instead a pool of pluripotent progenitor cells in the posterior end of the primitive streak that builds up the fetal-placental interface. The pluripotent cell pool condenses into a specific area of the proximal epiblast, namely the allantoic core domain (ACD), which extends the body axis posteriorly through the allantoic midline. The pluripotent cells in the ACD express all PGC markers and contribute to both embryonic and extraembryonic tissues. From this pluripotent population, it is suggested that PGC could be segregated later. PGC specification could take place for example during migration toward the genital ridge once evolutionarily conserved genes of germ line development, such as
3. PGC specification and migration in mammals other than the mouse
The embryo proper of most gastrulation-stage mammals, including humans, rabbits and pigs among others, has the shape of a flat disk with two cell layers: epiblast and hypoblast (equivalent to VE in mice) [39, 40, 41]. In the flat disk of non-rodent embryos, the epiblast contacts with the VE (hypoblast), and the ExE is absent. In basal rodents of the suborder Hystricognathi such as the guinea pig (
3.1. Human
Due to ethical and technical reasons, there is limited information on the origin of human PGCs in postimplantation embryos. PGCs have been described in human embryos at early somite stage in the dorsal wall of the yolk sac near the developing allantois [44, 45, 46]. Decades later, AP activity in presumably PGCs was observed by several groups in human embryos with 5–8 somites at a similar location. Using single cell analysis, human PGCs isolated at 4 weeks of development seem to express
3.2. Rabbit
In pregastrulation rabbit embryos,
On the other hand, PG-2 (a germ cell epitope) and
3.3. Plains vizcacha
A recent study in the basal Hystricognathi rodent
In an advanced stage of development, at neural plate stage, in the base of the allantois in the ectoderm and mesoderm after gastrulation, OCT4+ cells become restricted in number to a group of 6–8 cells, and they begin to express
Then, in the early- and late-head fold stages in mesoderm and endoderm tissues, the expression of
The spatiotemporal pattern of expression of germ line markers found in
4. The assembly of the mammalian ovary after PGC colonization
4.1. Germ cell proliferation in the fetal and postnatal ovary
The number of PGCs that colonize the genital ridges depends on the species. In mice, beginning with 100–145 PGCs at 8 days postconception (dpc), the number increases exponentially up to 15,000–20,000 oogonia per ovary at 15.5 dpc, the time of entry into meiosis and cessation of mitosis [33, 52, 53, 54, 55, 56]. A similar pattern of germ cell proliferation was described in rats [57]. In the basal rodent
After a few rounds of mitosis, colonizing PGCs, now referred to as oogonia, cease proliferation and enter a premeiotic phase, with downregulation of pluripotency-associated genes such as
In mice, entry into meiosis seems to be a synchronized event, with no overlapping between mitosis and meiosis. By 17 dpc, mitotic proliferation is finished and all germ cells initiate meiosis [65] entering meiotic prophase in a wave from the anterior to the posterior end of the ovary [64]. However, there is a marked asynchrony of germ cell development in the human ovary. The onset of meiosis occurs by week 11 of gestation [55], but mitosis continues in more peripherally located germ cells for many weeks thereafter, even when primordial follicles begin to form [64, 67]. In the rat, non overlapping mitosis and meiosis of germ cells occurs as in the mouse [68]. However, the basal rodent
The persistence of PGCs or oogonia in the postnatal ovary has been a matter of discussion throughout the twentieth century since Pearl and Schoppe [69] proposed, in 1921, that postnatal oogenesis might occur in the mammalian adult ovary. Three decades later, in an extensive review of the literature of the time, Zuckerman [70] advocated for the absence of oocyte renewal in the mature mammalian ovary, proposing that mammals are born with a finite nonrenewable oocyte pool, a perspective that was widely accepted for more than 50 years generating a useful framework in advancing our knowledge of ovarian dynamics in placental mammals. Nevertheless, this long-held dogma was challenged in 2004 by Tilly’s team [71] with the description of a small population of germ line stem cells in the adult ovary of the laboratory mouse. This observation refueled the possibility that neo-oogenesis could take place in the adult ovary of mammals and evidence for and against this possibility has accumulated over the recent years [72]. Although it has not been proved yet that ovarian stem cells may contribute to replenishment of the adult ovary if needed, the persistence of germ line stem cells has been independently proven in the human, mouse and rat models, as well as their ability to be manipulated
4.2. Germ cell death in the fetal and postnatal ovary
Death is a prominent feature of mammalian germ line development, with a predictable temporal and spatial pattern. In fetal life, direct germ cell depletion occurs by means of a constitutive massive germ cell death program, referred to as attrition [59, 60, 76, 77, 78, 79]. In adult life, germ cell demise is mainly the result of death of the supporting follicular cells, a process known as follicular atresia [64, 76, 77, 78].The main mechanism underlying germ cell attrition and follicular atresia requires the activation of a conserved intracellular program of cell death called apoptosis. The execution of the apoptotic program depends on the coordinated action of a group of genes that will activate as a signaling cascade in response to different stimuli. Depending on the source and type of the stimuli, apoptosis can be initiated through an extrinsic pathway, also referred to as the death receptor pathway, which includes the recognition of death ligands to their cell surface receptors [80] or the intrinsic or mitochondrial pathway, which is mainly regulated through the BCL2 protein family whose members are divided into three groups: proapoptotic proteins, antiapoptotic (or prosurvival) proteins and pore-forming proteins [81]. Extrinsic apoptosis molecules are mainly involved in final follicular regression and atresia and corpus luteum regression [82, 83].
The analysis of the spatial and temporal expression of members belonging to the
The causes that determine massive constitutive death of mammalian female germ cells are poorly understood. This massive elimination may avoid the persistence in the ovary of germ cells exhibiting nuclear or mitochondrial chromosomal/genetic defects [93]. Alternatively, death may relate to the exhaustion of germ cells acting as nurse cells to the surviving oocyte pool [94]. Finally, it has been suggested that massive death may enable the appropriate association between germ cells and pregranulosa cells during ovigerous cords or ovarian cyst breakdown, just before primordial follicles begin to form [95]. In any case, the balance between germ cell death and survival seems to be critical to preclude ovarian dysgenesis or premature ovarian failure and to ensure reproductive success.
Germ cell elimination occurs at different points of fetal development. There are three main waves of germ cell death: (i) at prophase and metaphase of proliferating oogonia, (ii) at pachytene of meiotic prophase I oocytes and (iii) at diplotene of meiotic prophase I oocytes [57, 59, 96]. The vast majority of germ cell death occurs during the second and the third waves. Thus, germ cells entering meiosis are particularly susceptible to cell death [55, 60].
In mice, the maximum number of germ cells is registered at the time of entry of primary oocytes into meiotic prophase. However, up to two-thirds of the germ cells are lost before the ovarian reserve is established just after birth [64, 97, 98]. In rats, germ cells proliferate to reach a peak of 64,000 oogonia at 17.5 dpc, but the number of oocytes falls down to about 39,000 at birth and 19,000 at 2 dpc [57, 96]. Humans display a similar dynamics of germ-cell elimination. After the germ cell peak number of 5–6×106 oocytes that occurs at 5 months postconception, there is a dramatic decline in germ cell numbers similar to that seen in mice and rats. By the time of birth, the number of germ cells drops dramatically to 1–2×106 [59, 61, 64, 96] (Figure 2).
Moreover, the process of germ-cell apoptosis continues during postnatal life through follicular atresia. In humans, only 300,000 oocytes survive at 7 years postpartum and fewer than 1000 are present in the years just prior to menopause [59, 61, 96].
4.3. Is massive female germ cell demise a constitutive trait for all mammalian species?
Once PGCs have colonized the fetal gonad, the final endowment that will constitute the oocyte reserve seems to depend largely on the balance between cell proliferation and death. Based on the results of germ cell death displayed by mouse, rat and human, it has been widely accepted that massive intraovarian elimination of germ cells is a constitutive attribute of mammalian ovary for the final establishment of the germinal reserve. After a period of high proliferation of colonizing PGCs to reach the maximal oocyte endowment of the species, the activation of the apoptotic pathway generates a point of inflection in the growth curve of the oocyte population that eliminates from 60 to 85% of newly formed oocytes depending on the species [54, 59, 97] (Figure 2). The comparable pattern following the elimination of germ cells quantified in mouse, rat and human, together with the recognition that apoptosis in fetal ovary is active in a few other mammals, proved sufficient to establish massive elimination as a general rule controlling the final oocyte endowment of the ovary in placental mammals.
Challenging this established rule, a quantitative estimate based on unbiased stereological methods showed that the mean germ cell number per ovary increases continuously from the early-developing fetal ovary up to 45–60 days after birth in the South American plains vizcacha,
Whether the vizcacha is just the exception that confirms the rule or it represents another strategy for establishing the germ cell endowment in mammals, we will have to wait for quantitative studies in a more representative number of placental mammals. Until then, the vizcacha is the first mammal so far described in which female germ line develops in the absence of constitutive massive germ cell elimination since the balance between pro- and anti-apoptotic
5. Concluding remarks
Our current knowledge regarding the origin and specification of PGCs and the establishment of the ovarian reserve in placental mammals comes by and large from model organisms, notably the mouse. The mouse model has erected as the paradigm for germ line development; however, studies in a few other species unveil differences that challenge the mouse gene network as an established path that may apply to all mammals.
The molecular pathway disclosed for the mouse embryo in the last fifteen years still lacks a final proof showing that the presumptive PGCs, originating early in the proximal epiblast of the egg cylinder, are the same cells that finally colonize the genital ridge later on development. Until this could be traced, alternative hypothesis proposing that PGCs may specify just before colonization from a migrating pluripotent cell population when evolutionarily conserved genes begin to express cannot be ruled out.
The peculiar morphology of the early-implanted mouse embryo, the egg cylinder, sets aside from most mammals that develop through a flat disk embryo. Hence, it is reasonable to suppose that the topographical difference of the gastrulating flat embryo may create a different morphological scenario for signaling and specification of PGCs. The current knowledge in flat embryos, such as those of human and vizcacha, supports a divergent molecular path from that of mouse.
Once the fetal gonad has been colonized by PGCs, it is widely accepted that a balance between proliferation and cell death determines the final oocyte reserve. Massive germ cell death is regarded as an intrinsic shared mechanism in the mammalian ovary regulating the establishment of the final oocyte pool. Nevertheless, only four species have been quantified at the moment and one of these four shows a continuous growth of the germinal population with a minimum cell death. If this is an exception to a general rule or an alternative strategy for establishing the oocyte pool remains unanswered for now.
At this time, we are still far from having a comprehensive knowledge on the possible variety of mechanisms regulating the origin and specification of PGCs and the establishment of the final oocyte reserve in placental mammals. The few species investigated so far seem to indicate that strategies that remain hidden in the great diversity of mammals have not yet been revealed. Comparative studies from different mammalian orders are still lacking and needed.
Acknowledgments
This study was supported by intramural grant program from Universidad Maimónides-Fundación Científica Felipe Fiorellino and PICT-1281-2014 granted to ADV from the Agencia Nacional de Promoción Científica y Tecnológica, Ministerio de Ciencia, Tecnología e Innovación Productiva, Argentina.
Abbreviations
PGCs | primordial germ cells |
ICM | inner cell mass |
ExE | Extraembryonic ectoderm |
VE | visceral endoderm |
TE | trophoectoderm |
ExM | extraembryonic mesoderm |
ACD | allantoic core domain |
hPGCL | human primordial germ cell-like |
pPGC | preprimordial germ cell |
References
- 1.
Saitou M, Barton SC, Surani MA. A molecular programme for the specification of germ cell fate in mice. Nature. 2002; 418 :293-300. DOI: 10.1038/nature00927 - 2.
Irie N, Tang WC, Surani MA. Germ cell specification and pluripotency in mammals: A perspective from early embryogenesis. Reprod Med Biol. 2014; 13 :203-215. DOI: 10.1007/s12522-014-0184-2 - 3.
Saitou M, Yamaji M. Germ cell specification in mice: Signaling, transcription regulation, and epigenetic consequences. Reproduction. 2010; 139 :931-942. DOI: 10.1530/REP-10-0043 - 4.
Bertocchini F, Chuva de Sousa Lopes SM. Germline development in amniotes: A paradigm shift in primordial germ cell specification. BioEssays. 2016; 38 :791-800. DOI: 10.1002/bies.201600025 - 5.
Mikedis MM, Downs KM. Mouse primordial germ cells: A reappraisal. International Review of Cell and Molecular Biology. 2014; 309 :1-57. DOI: 10.1016/B978-0-12-800255-1.00001-6 - 6.
Sheng G. Epiblast morphogenesis before gastrulation. Developmental Biology. 2015; 401 :17-24. DOI: 10.1016/j.ydbio.2014.10.003 - 7.
Beddington RS, Robertson EJ. Axis development and early asymmetry in mammals. Cell. 1999; 96 :195-209. DOI: 10.1016/S0092-8674(00)80560-7 - 8.
Bedzhov I, Zernicka-Goetz M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell. 2014; 156 :1032-1044. DOI: 10.1016/j.cell.2014.01.023 - 9.
Copp AJ, Cockroft DL, editors. Postimplantation Mammalian Embryos: A Practical Approach. 1st. Oxford: IRL Press-Oxford University Press; 1990. p. 420 - 10.
Nagy A, Gertsenstein M, Vintersten K, Behringer R, editors. Manipulating the Mouse Embryo: A Laboratory Manual. 3rd. New York: Cold Spring Harbor Laboratory Press; 2003. 100p - 11.
Lawson KA, Dunn NR, Roelen BA, Zeinstra LM, Davis AM, Wright CV, Korving JP, Hogan BL. Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes & Development. 1999; 13 :424-436 - 12.
Yamaji M, Seki Y, Kurimoto K, Yabuta Y, Yuasa M, Shigeta M, Yamanaka K, Ohinata Y, Saitou M. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nature Genetics. 2008; 40 :1016-1022. DOI: 10.1038/ng.186 - 13.
Vincent SD, Dunn NR, Sciammas R, Shapiro-Shalef M, Davis MM, Calame K, Bikoff EK, Robertson EJ. The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development. 2005; 132 :1315-1325. DOI: 10.1242/dev.01711 - 14.
Yabuta Y, Kurimoto K, Ohinata Y, Seki Y, Saitou M. Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biology of Reproduction. 2006; 75 :705-716. DOI: 10.1095/biolreprod.106.053686 - 15.
Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes & Development. 2008;22 :1617-1635. DOI: 10.1101/gad.1649908 - 16.
Ohinata Y, Payer B, O’Carroll D, Ancelin K, Ono Y, Sano M, Barton SC, Obukhanych T, Nussenzweig M, Tarakhovsky A. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature. 2005;436 :207-213. DOI: 10.1038/nature03813 - 17.
Weber S, Eckert D, Nettersheim D, Gillis AJ, Schafer S, Kuckenberg P, Ehlermann J, Werling U, Biermann K, Looijenga LH. Critical function of AP-2γ/TCFAP2C in mouse embryonic germ cell maintenance. Biology of Reproduction. 2010; 82 :214-223. DOI: 10.1095/biolreprod.109.078717 - 18.
Magnúsdóttir E, Dietmann S, Murakami K, Günesdogan U, Tang F, Bao S, Diamanti E, Lao K, Gottgens B, Surani AM. A tripartite transcription factor network regulates primordial germ cell specification in mice. Nature Cell Biology. 2013; 15 :905-915. DOI: 10.1038/ncb2798 - 19.
Tanaka SS, Matsui Y. Developmentally regulated expression of mil-1 andmil-2 , mouse interferon-induced transmembrane protein like genes, during formation and differentiation of primordial germ cells. Mechanisms of Development. 2002;119 :S261-S267 - 20.
Sato M, Kimura T, Kurokawa K, Fujita Y, Abe K, Masuhara M, Yasunaga T, Ryo A, Yamamoto M, Nakano T. Identification of PGC7 , a new gene expressed specifically in preimplantation embryos and germ cells. Mechanisms of Development. 2002;113 :91-94 - 21.
Payer B, Saitou M, Barton SC, Thresher R, Dixon JP, Zahn D, Colledge WH, Carlton MB, Nakano T, Surani MA. Stella is a maternal effect gene required for normal early development in mice. Current Biology. 2003; 13 :2110-2117 - 22.
Lange UC, Adams DJ, Lee C, Barton S, Schneider R, Bradley A, Surani MA. Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Molecular and Cellular Biology. 2008;28 :4688-4696. DOI: 10.1128/MCB.00272-08 - 23.
Bortvin A, Goodheart M, Liao M, Page DC. Dppa3/Pgc7/stella is a maternal factor and is not required for germ cell specification in mice. BMC Developmental Biology. 2004; 4 :2. DOI: 10.1186/1471-213X-4-2 - 24.
Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M, Lomeli H, Nagy A, McLaughlin KJ, Scholer HR. Oct4 is required for primordial germ cell survival. The EMBO Journal. 2004; 5 :1078-1083. DOI: 10.1038/sj.embor.7400279 - 25.
Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M, Vrana J, Jones K, Grotewold L, Smith A. Nanog safeguards pluripotency and mediates germline development. Nature. 2007; 450 :1230-1234. DOI: 10.1038/nature06403 - 26.
Campolo F., Gori M, Favaro R, Nicolis S, Pellegrini M, Botti F, Rossi P, Jannini EA, Dolci S. Essential role of Sox2 for the establishment and maintenance of the germ cell line. Stem Cells. 2013; 31 :1408-1421. DOI: 10.1002/stem.1392l - 27.
Leitch HG, Blair K, Mansfield W, Ayetey H, Humphreys P, Nichols J, Surani MA, Smith A. Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development. 2010; 137 :2279-2287. DOI: 10.1242/dev.050427 - 28.
Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, et al. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development. 1996; 122 :881-894 - 29.
Yoshimizu T, Sugiyama N, De Felice M, Yeom YI, Ohbo K, Masuko K, et al. Germline-specific expression of the Oct-4/ green fluorescent protein (GFP) transgene in mice. Development, Growth & Differentiation. 1999; 41 :675-684. DOI: 10.1046/j.1440-169x.1999.00474.x - 30.
Okamura D, Tokitake Y, Niwa H, Matsui Y. Requirement of Oct3/4 function for germ cell specification. Developmental Biology. 2008; 317 :576-584. DOI: 10.1016/j.ydbio.2008.03.002 - 31.
Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M. Oct4 is required for primordial germ cell survival. EMBO Reports. 2004; 5 :1078-1083. DOI: 10.1038/sj.embor.7400279 - 32.
Hart AH, Hartley L, Ibrahim M, Robb L. Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Developmental Dynamics. 2004; 230 :187-198. DOI: 10.1002/dvdy.20034 - 33.
Ginsburg M, Snow MH, McLaren A. Primordial germ cells in the mouse embryo during gastrulation. Development. 1990; 110 :521-528 - 34.
Lawson KA, Hage WJ. Clonal analysis of the origin of primordial germ cells in the mouse. Ciba Foundation Symposium. 1994; 182 :68-84 - 35.
Oktem O, Oktay K. The ovary. Anatomy and function throughout human life. Annals of the New York Academy of Sciences. 2008; 1127 :1-9. DOI: 10.1196/annals.1434.009 - 36.
Molyneaux KA, Stallock J, Schaible K, Wylie C. Time-lapse analysis of living mouse germ cell migration. Developmental Biology. 2001; 240 :488-498. DOI: 10.1006/dbio.2001.0436 - 37.
Anderson R, Fassler R, Georges-Labouesse E, Hynes RO, Bader B l, Kreidberg JA, Schaible K, Heasman J, Wylie C. Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads. Development. 1999; 126 :1655-1664 - 38.
Gomperts M, Garcia-Castro M, Wylie C, Heasman J. Interactions between primordial germ cells play a role in their migration in mouse embryos. Development. 1994; 120 :135-141 - 39.
Flechon JE. Morphological aspects of embryonic disc at the time of its appearance in the blastocyst of farm mammals [Sow, ewe and rabbit, scanning electron microscopy]. Scanning Electron Microscope (USA). 1978; 2 :541-546 - 40.
Barends PM, Stroband HW, Taverne N, te Kronnie G, Leën MP, Blommers PC. Integrity of the preimplantation pig blastocyst during expansion and loss of polar trophectoderm (Rauber cells) and the morphology of the embryoblast as an indicator for developmental stage. Journal of Reproduction and Fertility 1989; 87 :715-726 - 41.
Vejlsted M, Du Y, Vajta G, Maddox-Hyttel P. Post-hatching development of the porcine and bovine embryo—Defining criteria for expected development in vivo andin vitro . Theriogenology. 2006;65 :153-165. DOI: 10.1016/j.theriogenology.2005.09.021 - 42.
Chuva de Sousa Lopes SM, Roelen BA. Primordial germ cell specification: the importance of being “blimped”. Histology and Histopathology. 2008; 23 :1553-1561. DOI: 10.14670/HH-23.1553 - 43.
Leopardo NP, Vitullo AD. Early embryonic development and spatiotemporal localization of mammalian primordial germ cell-associated proteins in the basal rodent Lagostomus maximus . Scientific Reports. 2017;7 :594. DOI: 10.1038/s41598-017-00723-6 - 44.
De Felici M. Origin, migration, and proliferation of human primordial germ cells. In: Coticchio G, Albertini DF, De Santis L, eds. Oogenesis. 1st. London: Springer-Verlag; 2013. p. 19-37 - 45.
Witschi E. Migration of germ cells of human embryos from the yolk sac to the primitive gonadal folds. Contr Embryol Carnegie Inst. 1948; 209 :67-80 - 46.
Chen D, Gell JJ, Tao Y, Sosa E, Clark AT. Modeling human infertility with pluripotent stem cells. Stem Cell Research. 2017; 21 :187-192. DOI: 10.1016/j.scr.2017.04.005 - 47.
de Jong J, Stoop H, Gillis A, van Gurp R, van de Geijn G-J, de Boer M. Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. The Journal of Pathology 2008; 215 :21-30. DOI: 10.1002/path.2332 - 48.
Irie N. SOX17 is a critical specifier of human primordial germ cell fate. Cell. 2015; 160 :253-268. DOI: 10.1016/j.cell.2014.12.013 - 49.
Hopf C, Viebahn C, Püschel B. BMP signals and the transcriptional repressor BLIMP1 during germline segregation in the mammalian embryo. Development Genes and Evolution. 2011; 221 :209-223. DOI: 10.1007/s00427-011-0373-5 - 50.
Flechon JE. Morphological aspects of embryonic disc at the time of its appearance in the blastocyst of farm mammals [Sow, ewe and rabbit, scanning electron microscopy]. Scanning Electron Microscopy. 1978; 2 :541-546 - 51.
Aksoy I. Sox transcription factors require selective interactions with Oct4 and specific transactivation functions to mediate reprogramming. Stem Cells. 2013; 12 :2632-2646. DOI: 10.1002/stem.1522 - 52.
Chiquoine AD. The identification, origin and migration of the primordial germ cells in the mouse embryo. The Anatomical Record. 1954; 118 :135-146 - 53.
Fujimoto T, Miyayama Y, Futura M. The origin, migration and fine morphology of the human primordial germ cells. The Anatomical Record. 1977; 188 :315-330 - 54.
Hirshfield AN. Development of follicles in the mammalian ovary. International Review of Cytology. 1991; 124 :43-101 - 55.
Bendsen E, Byskov AG, Andersen CY, Westergaard LG. Number of germ cells and somatic cells in human fetal ovaries during the first weeks after sex differentiation. Human Reproduction. 2006; 21 :30-35 - 56.
Myers M, Morgan FH, Liew SH, Zerafa N, Gamage TU, Sarraj M, Cook M, Kapic I, Sutherland A, Scott CL, Strasser A, Findlay JK, Kerr JB, Hutt KJ. PUMA regulates germ cell loss and primordial follicle endowment in mice. Reproduction. 2014; 148 :211-219 - 57.
Beaumont HM, Mandl AM. A quantitative and cytological study of oogonia and oocytes in the foetal and neonatal rat. Proceedings of the Royal Society of London. Series B: Biological Sciences. 1961; 155 :557-579 - 58.
Inserra PIF, Leopardo NP, Willis MA, Freysselinard A, Vitullo AD. Quantification of healthy and atretic germ cells and follicles in the developing and post-natal ovary of the South American plains vizcacha, Lagostomus maximus : Evidence of continuous rise of the germinal reserve. Reproduction. 2014;147 :199-209 - 59.
Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proceedings of the Royal Society of London. Series B: Biological Sciences. 1963; 158 :417-433 - 60.
Baker TG, Franchi LL. The fine structure of oogonia and oocytes in human ovaries. Journal of Cell Science. 1967; 2 :213-224 - 61.
Wise PM, Priess J, Kashon ML. Menopause: the aging of multiple pacemakers. Science. 1996; 273 :67-70 - 62.
Mamsen LS, Lutterodt MC, Andersen EW, Byskov AG, Andersen CY. Germ cell numbers in human embryonic and fetal gonads during the first two trimesters of pregnancy: Analysis of six published studies. Human Reproduction. 2011; 26 :2140-2145 - 63.
Childs AJ, Kinnell HL, He J, Anderson RA. LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary. Stem Cells and Development. 2012; 21 :2343-2349 - 64.
Findlay JK, Hutt KJ, Hickey M, Anderson RA. How is the number of primordial follicles in the ovarian reserve established? Biology of Reproduction. 2015; 93 (5):111,1-111,7 - 65.
Speed RM. Meiosis in the foetal mouse ovary. I. An analysis at the light microscope level using surface-spreading. Chromosoma. 1982; 85 :427-437 - 66.
McLaren A. Primordial germ cells in the mouse. Developmental Biology. 2003; 262 :1-15 - 67.
Fulton N, Martins da Silva SJ, Bayne RAL, Anderson RA. Germ cell proliferation and apoptosis in the developing human ovary. Journal of Clinical Endocrinology and Metabolism. 2005; 90 :4664-4670 - 68.
Hirshfield AN. Relationship between the supply of primordial follicles and the onset of follicular growth in rats. Biology of Reproduction. 1994; 50 :421-428 - 69.
Pearl R, Schoppe WF. Studies on the physiology of reproduction in the domestic fowl. The Journal of Experimental Zoology. 1921; 34 :101-111 - 70.
Zuckerman S. The number of oocytes in the mature ovary. Recent Progress in Hormone Research. 1951; 6 :63-109 - 71.
Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004; 428 :145-150 - 72.
Tilly JL, Niikura Y, Rueda BR. The current status of evidence for and against postnatal oogenesis in mammals: A case of ovarian optimism versus pessimism? Biology of Reproduction. 2009; 80 :2-12 - 73.
Zou K, Hou L, Sun K, Xie W, Wu J. Improved efficiency of female germline stem cell purification using fragilis-based magnetic bead sorting. Stem Cells and Development. 2011; 20 :2197-2204 - 74.
White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nature Medicine. 2012; 18 :413-421 - 75.
Zhou L, Wang L, Kang JX, Xie W, Li X, Wu C, et al. Production of fat-1 transgenic rats using a post-natal female germline stem cell line. Molecular Human Reproduction. 2014; 20 :271-281 - 76.
Coucouvanis EC, Sherwood SW, Carswell-Crumpton C, Spack EG, Jones PP. Evidence that the mechanism of prenatal germ cell death in the mouse is apoptosis. Experimental Cell Research. 1993; 209 :238-247 - 77.
De Pol A, Vaccina F, Forabosco A, Cavazzuti E, Marzona L. Apoptosis of germ cells during human prenatal oogenesis. Human Reproduction. 1997; 12 :2235-2241 - 78.
Kaipia A, Hsueh AJ. Regulation of ovarian follicle atresia. Annual Review of Physiology. 1997; 59 :349-363 - 79.
Morita Y, Tilly JL. Oocyte apoptosis: Like sand through an hourglass. Developmental Biology. 1999; 213 :1-17 - 80.
Sheikh MS, Huang Y. Death receptors activation complexes: It takes two to activate TNF receptor 1. Cell Cycle. 2003; 2 :550-552 - 81.
Willis SN, Adams JM. Life in the balance: How BH3-only proteins induce apoptosis. Current Opinion in Cell Biology. 2005; 17 :617-625 - 82.
Kondo H, Maruo T, Peng X, Mochizuki M. Immunological evidence for expression of the Fas antigen in the infant and adult human ovary during follicular regression and atresia. The Journal of Clinical Endocrinology and Metabolism. 1996; 81 :2702-2710 - 83.
Albamonte MS, Albamonte MI, Vitullo AD. Germline apoptosis in the mature human ovary. Journal of Medical Research and Science. 2012; 2 :134-143 - 84.
Aitken RJ, Findlay JK, Hutt KJ, Kerr JB. Apoptosis in the germ line. Reproduction. 2011; 141 :139-150 - 85.
De Felici M. Bcl-2 and Bax regulation of apoptosis in germ cell during prenatal oogenesis in the mouse embryo. Cell Death and Differentiation. 1999; 6 :908-915 - 86.
Kim MR, Tilly JL. Current concepts in Bcl-2 family member regulation of female germ cell development and survival. Biochimica et Biophysica Acta. 2004; 1644 :205-210 - 87.
De Felici M, Klinger FG, Farini D, Scaldaferri ML, Iona S, Lobascio M. Establishment of oocyte population in the fetal ovary: Primordial germ cell proliferation and oocyte programmed cell death. Reproductive Biomedicine Online. 2005; 10 :182-191 - 88.
Tilly JL. The molecular basis of ovarian cell death during germ cell attrition, follicular atresia, and luteolysis. Frontiers in Bioscience. 1996; 1 :1-11 - 89.
Tilly JL, Tilly KI, Perez GI. The genes of cell death and cellular susceptibility to apoptosis in the ovary: A hypothesis. Cell Death and Differentiation. 1997; 4 :180-187 - 90.
Albamonte MS, Willis MA, Albamonte MI, Jensen F, Espinosa MB, Vitullo AD. The developing human ovary: immunohistochemical analysis of germ-cell specific VASA protein, BCL-2/BAX expression balance and apoptosis. Human Reproduction. 2008; 23 :1895:1901 - 91.
Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995; 270 :96-99 - 92.
Ratts VS, Flaws JA, Kolp R, Sorenson CM, Tilly JL. Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad. Endocrinology. 1995; 136 :3665-3668 - 93.
Tilly JL. Commuting the death sentence: How oocytes strive to survive. Nature Reviews. Molecular Cell Biology. 2001; 2 :838-848 - 94.
Pepling ME, de Cuevas M, Spradling AC. Germline cysts: A conserved phase of germ cell development? Trends in Cell Biology 1999; 9 :257-262 - 95.
Guigon CJ, Magre S. Contribution of germ cells to differentiation and maturation of the ovary: Insights from models of germ cell depletion. Biology of Reproduction. 2006; 74 :450-458 - 96.
Matova N, Cooley L. Comparative aspects of animal oogenesis. Developmental Biology. 2001; 231 (2):291-320 - 97.
Flaws JA, Hirshfield AN, Hewitt JA, Babus JK, Furth PA. Effect of Bcl-2 on the primordial follicle endowment in the mouse ovary. Biology of Reproduction. 2001; 64 :1153-1159 - 98.
Kerr JB, Myers M, Britt KL, Mladenovska T, Findlay JK. Quantification of healthy follicles in the neonatal and adult mouse ovary: Evidence for maintenance of primordial follicle supply. Reproduction. 2006; 132 :95-109 - 99.
Leopardo NP, Jensen F, Willis MA, Espinosa MB, Vitullo AD. The developing ovary of the South American plains vizcacha, Lagostomus maximus (Mammalia, Rodentia): Massive proliferation with no sign of apoptosis-mediated germ cell attrition. Reproduction. 2011;141 :633-641 - 100.
Jensen FC, Willis MA, Albamonte MS, Espinosa MB, Vitullo AD. Naturally suppressed apoptosis prevents follicular atresia and oocyte reserve decline in the adult ovary of Lagostomus maximus (Rodentia, Caviomorpha). Reproduction. 2006;132 :301-308