The programmed death of fetal oocytes and the correlated surveillance mechanisms : Reproductive and Developmental Medicine

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Review Article

The programmed death of fetal oocytes and the correlated surveillance mechanisms

Zhou, Jia-Qi1; Wang, Wen-Ji2; Xia, Guo-Liang1,3; Wang, Chao1,*

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Reproductive and Developmental Medicine: September 2022 - Volume 6 - Issue 3 - p 181-193
doi: 10.1097/RD9.0000000000000016
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In female mammals, the perinatally established primordial follicle pool is the only source of oocytes throughout the reproductive cycle[1,2]. Shortly after birth, primordial follicles are sacrificed gradually, and the pool size shrinks irreversibly with age. As a result, oocyte quality declines, and the reproductive life span reduces with age[3,4], which emphasizes the importance of the high-quality available oocyte reserve to childbearing females. Primary ovarian insufficiency (POI) affects at least 1% of women under the age of 40 years worldwide[5]. POI is a clinical term for premature ovarian failure that is characterized by the disappearance of menstrual cycles associated with premature follicular depletion[6]. Currently, many human gene mutations have been reported in patients with POI[7]. Some of the most studied genes are listed in Table 1. Thus, uncovering the rhythms of primordial follicle formation, depletion, and reservation is pivotal to help understand the pathological mechanisms and help these patients.

Table 1 - Mutated genes associated with POI.
Gene (human) Mutation (s) Phenotype References
Fshr c.662T>G 1 Japanese female with primary amenorrhea [121]
c.1255G>A 1 Finnish female with primaryamenorrhoea
Gdf9 c.199A>C, c.646G>A 6 of 127 patients with POI (4.7%) [122]
Bmp15 c.704A>G 2 sisters with hypogonadotropic ovarian failure [123]
Mcm8 c.446C>G 3 sisters with primary amenorrhoea and hypothyroidism [124]
Msh5 g.2547C>T 2 individuals of 41 Caucasian women with POI (4.9%) [125]
Stag3 c.1573 + 5G>A 2 affected sisters manifested with primary amenorrhoea [126]
Sgo2 c.1453_1454delGA 4 POI members of a family [127]
Polr3h c.149A>G 2 of 11 families with idiopathic POI (18.2%) [128]
Nobox c.907C>T, c.271G>T, c.349C>T, c.1025G>C, c.1048G>T 12 individuals of 178 POI patients (6.2%) [129]
Foxl2 c.738C>T, c.773C>G 2 individuals of 80 POI patients (2.5%). [130]
Foxo3 c.71C>A, c.140C>T, c.184G>A, c.1652C>T, c.1697C>G 15 individuals of 114 Chinese women with POI (13.2%) [131]
Figla c.11C> A, c.15-36del, c.419-421delACA 4 individuals of 100 Chinese women with POI (4.0%) [132]
Bnc1 c.1065_1069del, c.1595T>C A family case and 4 of 82 patients with POI (4.9%) [133]
POI: primary ovarian insufficiency.

In fetal ovaries, the number of oocytes reaches a peak when primordial germ cell (PGC) mitosis is completed[8]. By then, multiple germ cells share a cytoplasmic cyst structure due to the rapid and incomplete mitosis of oogonia[9]. With the initiation and cessation of meiosis prophase I (MPI), oocytes undergo homologous chromosome synapsis and recombination followed by the formation of numerous double-strand breaks (DSBs)[10]. In humans, over 90% of natural conceptions are of meiotic origin, and the majority are caused by errors in meiosis I[11]. As a result, not all oocytes possess a similar fate of being enclosed by surrounding pregranulosa cells and forming primordial follicles perinatally. Instead, only 1/3rd of the oocytes, arrested at the diplotene stage, form primordial follicles, while the remainder are lost during fetal development, severely diminishing the germ cell resources at the physiological level[12].

In conclusion, the quantity and quality of mature oocytes are pivotal for human reproduction. The genetic and epigenetic background determines the potential for embryo development once the selected maturated oocytes are fertilized. Thus, thoroughly explaining how and why only a small portion of oocytes lives is an interesting topic that needs substantial research.

Cell death is a complex process that is both regulated and circumscribed[13]. As one of programmed cell death (PCDs) that occurs during embryonic development, apoptosis-induced PCD is active in various tissues and organs in fetuses. It is also closely related to oocyte loss in the fetal ovary. However, apoptosis is not the only cause of PCD. Autophagy, also known as type II PCD, regulates cell death via apoptosis[14]. Autophagy, as part of the intracellular homeostasis mechanisms, is an evolutionarily conserved and physiologically important process regulating the turnover of intracellular material in eukaryotes by degrading functionally redundant or damaged cells and organelles[15]. The two pathways of PCDs are interrelated and mutually regulated. In this paper, the reasons why apoptosis and autophagy are active in oocyte PCDs during the process of primordial follicle formation have been primitively explained, which sheds light on systematically answering the unsolved questions of POI.

After reviewing the involvement and progress of autophagy and apoptosis in determining oocyte death before primordial follicle pool establishment, we concluded that at least three physiological protective mechanisms exist that prevent premature oocyte PCDs via either apoptosis or autophagy in fetal ovaries[16–18]. This is thought to be part of a conserved oocyte quality control strategy to ensure the quality of primordial follicles.

The progress of primordial follicle formation in mammals

According to existing studies, the formation of primordial follicles in mammals requires at least three prerequisites: oocytes that are blocked in the first meiotic prophase, pregranulosa cells expressing Forkhead Box L2 positive (FOXL2+) protein, and constant communication and interaction between the two types of cells[19]. We have summarized the molecular mechanisms of primordial follicle formation in recent years in Fig. 1.

Fig. 1.:
(A) Primitive molecular regulatory network of primordial follicle formation. (1) LGR5+ pregranulosa cells differentiate into FOXL2+ pregranulosa cells. CAV1, ADAM10, and SP1 regulate the proliferation of LGR5+ pregranulosa cells via the Notch2 pathway. (2) Oocyte meiotic progression. PGCs enter meiosis under the induction of retinoic acid (RA) and are blocked at the dictyotic phase before primordial follicle formation, in which CYP51 and cAMP promote meiosis, whereas progesterone (P4) is an inhibitory factor. Germ cyst breakdown is accompanied by the loss of a large number of oocytes via either apoptosis or autophagy. GSK3β, LSD1, and XIAP are potential protectors for monitoring the developmental quality of oocytes before primordial follicles are formed. Paracrine factors, such as inhibin, follistatin, and TGFβ1, as well as intracytoplasmic molecules, such as JNK, are responsible for controlling germ cyst breakdown. In Drosophila and Caenorhabditis elegans, B-body, LINE1, and patronin are indicators of oocyte survival. (3) Communication and interaction between granulosa cells and oocytes. Oocytes release S100A8 to attract granulosa cell migration. Multiple gap junctions (GJs) have been established to promote primordial follicle formation. Proteins such as RAC1, TGF-β, N-Cad/E-cad, activin A, BDNF, and NGF actively participate in promoting primordial follicle formation. ADAM10: a disintegrin and metalloproteinase domain 10; BDNF: brain-derived neurotrophic factor; cAMP: cyclic adenosine monophosphate; CAV1: caveolin 1; CYP51: cytochrome P450 family member 51; E-cad: E-cadherin; FOXL2+: Forkhead Box L2 positive; GJs: gap junctions; GSK3β: glycogen synthase kinase 3 beta; JNK: c-Jun N-terminal kinase; LGR5+: leucine-rich repeat-containing g-protein-coupled receptor 5-positive; LINE1: long interspersed nuclear element-1; LSD1: lysine-specific demethylase 1; N-Cad: N-cadherin; NGF: nerve growth factor; P4: progesterone; PGCs: primordial germ cells; RA: retinoic acid; RAC1: Ras-related C3 botulinum toxin substrate 1; S100A8: S100 calcium binding-protein A8, also known as chemotactic cytokine CP-10; SP1: specificity protein 1/krüppel-like factor 1; TGF-β: transforming growth factor beta; TGF-β1: transforming growth factor beta 1; XIAP: X-linked inhibitor of apoptosis.

The understanding of the formation mechanism of the female primordial follicle reservoir remains superficial despite recent efforts[19]. Under physiological conditions, PGCs migrate to the genital ridge before differentiating into oogonia cells[20,21]. Once settled, the oogonia cells initiate mitosis, facilitating the surge of the germ cell number in a very short window. Meanwhile, a structure called the germ line cyst arises in the ovarian tissue, in which the cytoplasm of different germ cells is linked by intercellular bridges due to the incomplete division of the oocyte[22]. Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells by intercellular bridges, and formation a structure of Balbiani body (B-body) including centrosomes, Golgi, and mitochondria[23]. However, there is still a lack of detailed subcellular illustration of the dynamic aspects of these cysts that hinders a profound understanding of the reason why and how the cysts actively determine the fate of individual germ cells in each cyst.

With the cessation of mitosis, meiosis of the oogonia begins. Retinoic acid (RA) produced from both the mesonephros and fetal ovary initiates meiosis[24,25]. Before germ line cyst breakdown, most oocytes were blocked at the diplotene stage of the first meiotic prophase. During this period, the outer layer of the cysts was surrounded by somatic cells[26,27]. Eventually, several FOXL2+ pregranulosa cells that are differentiated from leucine-rich repeat-containing g-protein-coupled receptor 5-positive (LGR5+) somatic stem cells gradually envelop the individual oocyte to assemble into a primordial follicle structure[28].

The signals that participate in the regulation of primordial follicles are complex and lack systematic studies. Briefly, transforming growth factor beta family members[29], including anti-Müllerian hormone, differentiation factors, bone morphogenetic proteins, Activin A, and TGF-β, are active in the formation of primordial follicles. Neurotrophins (NTs) may also be involved in this process[30,31].

The programmed meiosis of oocytes in the fetal ovary

The initiation and cessation of oocyte MPI in the fetal ovary are essential to ensure primordial follicle formation. Once RA initiates meiosis, the oocyte undergoes changes in the leptotene, zygotene, pachytene, and diplotene phases and eventually halts at the dictyate stage of the diplotene phase, which is believed to be a prerequisite for primordial follicle formation[32,33].

As the most critical component in primordial follicle formation, oocytes secrete several specific molecules, such as S100 calcium-binding protein A8 (S100A8), kit proto-oncogene, receptor tyrosine kinase proto-oncogene, receptor tyrosine kinase ligand (KITL), and Jagged canonical notch ligand 1 (Jagged1), necessary for primordial follicle formation by communicating with pregranulosa cells[34–36]. Oocyte-specific transcription factors are involved in primordial follicle formation[37]. At least eight oocyte-specific transcription factors derived from oocytes, namely Figlα, Sohlh1, Lhx8, Nobox, Stat3, Tbpl2, Dynll1, and Sub1, actively participate in determining the fate of oogonia and exert their respective influences on primordial follicle formation[38]. However, it is unclear what types of key molecules outside or inside the oocytes are specifically responsible for stimulating the activities of transcription factors. For instance, double mutations of growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) result in multiple oocyte follicles in the ovary[39]. Additionally, Rac family small GTPase 1, a molecular switch that regulates the conversion of guanosine triphosphate and guanosine diphosphate, is progressively expressed at a higher level in response to germ line cyst breakdown. The inhibition of Rac1 impairs primordial follicle formation in cultured fetal mouse ovaries, possibly by regulating the expression of Gdf9, Bmp15, and Jagged1[34]. Additionally, Jagged1 is one of the most important ligands of Notch signaling in regulating the behavior of pregranulosa cells. Although these primitive findings are far from unveiling the myth of the active involvement of oocytes in primordial follicle formation, they highlight the importance of communication established between germ cells and ovarian somatic cells during the course.

The structural changes that occur in oocytes significantly contribute to the formation and determination of the number of primordial follicles. Importantly, the B-body is essential for the formation and survival of the primordial follicle[23]. It is speculated that germ cells lacking the B-body will eventually die and therefore affect the size of the ovarian reserve[40,41]. In mice, approximately 6.4 germ cells survive from the initial 30 sister germ cells within a cyst. The remaining cells may develop into nurse cells that do not have B-body structures but are responsible for feeding the developing oocyte within a cyst[23]. Interestingly, according to the most recent report in Drosophila, nurse cells are hijacked by a group of retrotransposons, such as I-elements, to ensure propagation in the host genome during oogenesis[42]. The I-element is similar to that of the mammalian non-long terminal repeat retrotransposon long interspersed nuclear element-1. The I-element in nurse cells produces virus-like particles that migrate in a microtubule-dependent manner to interconnected oocytes that eventually survive. Interestingly, they rarely integrate into nurse cells themselves, which are highly polyploid and eventually undergo apoptosis[42]. Unfortunately, it is still unclear whether such an interesting microtubule-mediated transportation working model can explain the formation and movement of the B-body during oogenesis in mammals. Similarly, in Drosophila, patronin is a homologous protein of calmodulin-regulated spectrin-associated protein in mammals. Patronin is one of the potential indicators of the surviving oocytes[43]. Whether similar functional molecules and mechanisms are observed in mammalian oocytes is unknown.

The development of pregranulosa cells in the fetal ovaries

The differentiation and proliferation of fetal ovarian somatic cells synchronized with oocyte development are vital to ensure the proper assembly of primordial follicles[44,45]. The origin of different somatic cells in the fetal ovary is versatile. Pregranulosa cells are mainly derived from mesonephric surface epithelial cells that differentiate into gonadal-ridge epithelial-like cells[46]. These epithelial-like cells develop into surface epithelial and pregranulosa cells. Eventually, the pregranulosa cells differentiate into FOXL2+ granulosa cells before participating in primordial follicle formation[47].

Alongside the oocyte entering meiosis, somatic cells differentiate simultaneously, preparing for primordial follicle formation[44]. Oocytes recovered from 17.5 dpc (days post coitum) fetal mice ovary could only interact with 17.5 dpc ovarian somatic cells to form primordial follicle-like structures in vitro[44]. LGR5+ cells derived from ovarian epithelial-like cells are the key cell type for differentiation into FOXL2+ granulosa cells[48]. Further, the differentiation process of FOXL2+ pregranulosa cells is controlled by Notch protein in mice. Interestingly, the disintegrin and metalloproteinase domain-containing protein 1 protein, a cell surface sheddase, and transcription factor specificity protein 1/krüppel-like factor 1, which is active within LGR5+ cells, are both important regulators of pregranulosa cell development by regulating the activity of Notch protein or the expression of Notch, respectively[49]. A most recent study by Niu and Spradling[50] found that pregranulosa cells develop distinctly in mice. Two types of pregranulosa cells are available in fetal mouse ovaries: bipotential pregranulosa (BPG) and epithelial pregranulosa (EPG). Briefly, BPG cells express Forkhead Box L2 (FOXL2) at 12.5 dpc, whereas EPG cells express LGR5 at 12.5 dpc or earlier and begin expressing FOXL2 until after birth. By 19.5 dpc, EPG cells had differentiated in the cortex into granulosa cells of quiescent primordial follicles. In contrast, BPG cells differentiate into flat granulosa cells, which are activated to form cubes[50]. In humans, the mutation of FOXL2 correlates with POI[51], whereas in mice, Foxl2 knockout causes failure of flattened granulosa cells to transition to cuboidal after birth[52].

All of these studies imply not only the complexity of pregranulosa cell development but also the sign of the spatiotemporal development of pregranulosa cells. However, how ovarian somatic cells react to surrounding signals remains poorly understood.

Mutual communication between the oocyte and the pregranulosa cells

Many signaling molecules provided by either germ cells or ovarian somatic cells in the ovarian microenvironment are involved in modulating primordial follicle formation[19]. For example, cell-to-cell adhesion exists either among pregranulosa cells or between pregranulosa cells and oocytes and is essential for the proper assembly of the primordial follicle. Among these proteins, E-cadherin (E-Cad) and N-cadherin (N-Cad) are thought to be the main calmodulins that work mutually in the ovarian tissues[53]. In mice, fetal ovaries show the highest expression of E-Cad before germ line cyst breakdown. Within each primordial follicle, E-Cad in the membrane area of the oocyte interacts with N-Cad located in the granulosa cell to stabilize the follicular structure[54]. Furthermore, E-Cad is thought to be important in maintaining the dormant state of primordial follicles by regulating the expression of newborn ovary homeobox protein by preventing β-catenin from entering the nucleus[55].

Gap junction (GJ) established between germ cells, and pregranulosa cells are important for intercellular material exchange during primordial follicle formation[56,57]. According to our findings, many GJ family members are present in mouse fetal ovaries as early as 17.5 dpc[58]. Disruption of the GJ in the fetal ovary results in impaired primordial follicle assembly in mice in vitro[59]. Despite establishing the importance of the GJ within primordial follicles, it is difficult to clarify the exact functions of each GJ protein. This is not only because there is a lack of sufficient and specific antibodies that can identify the individual functions of every GJ present in fetal ovaries but also because the compensatory action among the members of GJ may be active. More animal models are needed to evaluate the importance of the GJ during primordial follicle formation.

Identifying the mechanism by which pregranulosa cells sense the existence of a well-prepared oocyte is challenging. According to existing data, S100A8, a chemokine, is specifically expressed in oocytes in germ line cysts and significantly promotes the migration of FOXL2+ pregranulosa cells[37]. Thus, a well-prepared oocyte may recruit FOXL2+ pregranulosa cells to move toward itself, thus facilitating primordial follicle formation[37]. Besides, KITL secreted by oocytes may be attributed to recruiting FOXL2+ pregranulosa. In vitro, blocking KIT (KIT proto-oncogene, receptor tyrosine kinase) signaling impairs germ line cyst breakdown, whereas the addition of KITL recombinant protein activates KIT signaling within pregranulosa cells and promotes primordial follicle formation[60]. Additionally, NTs may be important in regulating primordial follicle formation[61,62]. The number of oocytes in the fetal mouse ovary is significantly reduced, and primordial follicle formation is blocked when either nerve growth factor or its receptor neurotrophic receptor tyrosine kinase 1 is inhibited[63].

TGF-β family members of activins were found to accelerate the first meiotic process of oocytes to promote primordial follicle formation and induce meiotic initiation synergistically with RA[64]. Follistatin (FST) is a widely expressed protein that was originally isolated from gonadal fluid. FST has three protein isomeric forms that perform different physiological functions in the organism. In FST288-only female mice, the ovary contains numerous germ line cysts, accompanied by a large loss of germ cells at birth due to apoptosis. Loss of the FST303 and FST315 isoforms leads to excess primordial follicles with accelerated demise, resulting in the premature cessation of ovarian function[65,66].

In conclusion, an established ordered structure and efficient oocyte-granulosa cell communication are crucial for ensuring primordial follicular formation.

Oocytes loss is dominant before primordial follicle pool establishment

In females, the peak number of oocytes reserved in the ovary is achieved at the onset of the first meiotic division. The number of oocytes then decreases rapidly during the primordial follicle formation. Under physiological conditions, more than half the oocytes are selectively eliminated during the embryonic period or around the time of birth. The total number of germ line cysts together with individual germ cells reaches the summit at approximately 14.5 dpc in mice and 20 weeks postconception in humans[8,9]. After birth, although the depletion speed becomes slower than in the fetal period, the number shrinks continuously and is non-renewable over the following years or decades[67]. Whenever the oocyte reserve is nearly exhausted, the ovary rapidly ages as a woman enters menopause[68].

Although the regulatory mechanisms and biological significance of the rise and fall in oocyte number remain unclear, studies have suggested that apoptosis and autophagy are actively involved in regulating the number of oocytes in the fetal ovary[69–71]. In line with these findings, studies from other labs and ours emphasize the significance of intermediate molecules that are responsible for either provoking or executing oocyte PCDs, which are summarized in Tables 2 and 3. For instance, we found that both glycogen synthase kinase 3 beta (GSK-3β)–mediated apoptosis and lysine-specific demethylase 1 (LSD1)–mediated autophagy have a major role in determining the number of oocytes from the initiation to completion of primordial follicle formation in perinatal mouse ovaries[16,17]. Additionally, X-linked inhibitor of apoptosis (XIAP) may actively preserve oocytes[18]. These findings imply that different backgrounds of PCDs possibly existed simultaneously in the ovaries of perinatal mice, which could be helpful to address the underlying mechanisms of germ cell fate and primordial follicle pool size were fixed under physiological conditions.

Table 2 - Apoptotic-related genes involved in the dynamics of follicle development.
Gene (mouse) Action Phenotype and function References
Bax Proapoptosis More primordial follicles in newborn ovaries after knockout [134]
Bok Proapoptosis After the knockout, no significant difference in follicle number [135]
Bad Proapoptosis Overexpression induces granulosa cells apoptosis [136]
Bak Proapoptosis There is no significant difference in follicle number in knockout mice. Bak and Bok double induce an increase of follicle number [137]
Bbc3 Proapoptosis Increase follicle numbers in knockout mice [82]
Pmaip1 Proapoptosis There is no significant difference in follicle number in knockout mice [138]
Casp2 Proapoptosis Increase follicle numbers in knockout mice [88]
Tnfr1 Proapoptosis There is no significant difference in follicle number in knockout mice [86]
Tnfr2 Proapoptosis Increase primary follicle numbers in knockout mice [87]
L1td1 Proapoptosis Overexpression Line-1 reduced survival rates of fetal oocytes [139]
Bmp4 Prosurvival Overexpression induces granulosa cells’ survival [140]
Mael Prosurvival Increased fetal oocyte attrition and diminished oocyte reserve in maelstrom null ovaries [95]
Bcl2 Prosurvival There is no significant difference in follicle number in knockout mice [60]
Mcl1 Prosurvival Increased oocyte apoptosis and premature ovarian failure in knockout mice [92]
Birc1, Birc5, Birc6, Birc7 Prosurvival Neuronal apoptosis inhibitory protein prevents granulosa cell death in ovarian folliculogenesis. The separate roles of its family members are not known [141]
Lif Prosurvival LIF treatment increased the primary follicles [142]
Igf1 Prosurvival Igf1 deletion mice are infertile with follicular development arrested at the late pre-antral stage [143]
Kit Prosurvival Promote the survival of primordial germ cells [35]
Kitl Prosurvival Promote the primordial follicle activation [35]
Gata4, Gata6 Prosurvival Sf1-are specific knockdown of Gata4 and Gata6 in embryonic gonadal cells results in impaired somatic cell proliferation and impaired cysts breakdown [144]
Tgfb1 Prosurvival Decrease the number of germ cells [29]
Bmp15 Prosurvival Promote primordial follicle assembly [145]
Gdf9 Prosurvival Promote primordial follicle assembly [39]
Smad2/3 Prosurvival Promote the primordial follicle activation [146]
Bdnf, Gdnf, Ngf Prosurvival Promote the primordial follicle activation [147]
Gsk3b Prosurvival Promote primordial follicle assembly and reduce germ cell apoptosis [16]
LIF: leukemia inhibitory factor.

Table 3 - Autophagy-related genes involved in the dynamics of follicle development.
Gene (mouse) Action Function References
Ampk Prosurvival Energy deficit of the cell as a start to induce autophagy [107]
Mtor Prosurvival Intracellular energy-sensing molecules [107]
Kdm1a Prosurvival Inhibition LSD1, promotion of autophagy; overexpression LSD1 reduced oocytes loss [17]
Nlrp3 Prosurvival Ablation NLRP3 improved the survival and autophagy rates in ovaries [100]
Nrf2 Prosurvival Reducing oxidative stress and cell autophagy [10]
Becn1 Proautophagy Becn1+/− ovaries lose germ cells [69]
Ulk1/ Ulk2 Proautophagy Autophagy-related genes [148]
Uvrag Proautophagy Autophagy-related genes [148]
Atg3, Atg4a, Atg5, Atg12 Proautophagy Autophagy-related genes [148]
Atg7 Proautophagy Atg7+/− ovaries lack discernable germ cells at postnatal day 1 [69,105]
Atg9a Proautophagy ATG9A variants led to a decrease in autophagosome biosynthesis and POI [104]
Map1lc3b Proautophagy Autophagy-related genes [149]
Sqstm1 Proautophagy Autophagy-related genes [17]
ATG9A: autophagy-related protein 9A; LSD1: lysine-specific demethylase 1; NLRP3: nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3; POI: primary ovarian insufficiency.

Apoptosis-related oocytes loss

Apoptosis helps eliminate oocytes with quality defects, such as unsuccessful repair of deoxyribonucleic acid damage produced during meiosis[72,73]. Both DSBs, DSB-independent and DSB-dependent apoptosis responses, are observed in fetal oocytes through various mechanisms[74]. Cumulative studies have shown that mutations in Ataxia telangiectasia mutated (ATM), SPO11, RAD51, and Mei4, which are associated with chromosome synapsis and crossover, linkage, or DNA repair, are associated with oocyte quality and lead to oocyte apoptosis shortly after birth[75–78]. The detailed mechanisms that modulate apoptosis are reviewed below.

First, meiotic sex chromosome inactivation (MSCI) has been proposed to determine the fate of oocytes[74]. MSCI is a meiotic DSB-independent response that induces apoptosis. Generally, the X chromosome lacks a homolog; therefore, homologous synapsis cannot be achieved. In females, the inactive X chromosome of oogonia is generally reactivated; thus, both X chromosomes are active throughout the MPI[79,80]. X frequently folds back on itself and achieves nonhomologous self-synapsis, thus evading MSCI and ensuring oocyte survival[79]. However, in the case of presence of only one sex chromosome monosomy, MSCI of the X chromosome causes perinatal oocyte loss. Therefore, oocytes that survive should achieve self-synapsis by expressing pachytene-critical genes, since the beginning of the pachytene stage is marked by the completion of synapsis and repair of DSBs[80].

Moreover, several prosurvival and proapoptotic molecules are involved in ovarian apoptosis, and the delicate balance between them determines the final fate of primordial follicle cells (Table 2). For example, the p53 upregulated modulator of apoptosis (PUMA) is involved in oocyte loss[81]. PUMA is a proapoptotic effector with high affinity for the apoptotic protein family B-cell lymphoma/leukemia 2 (BCL2). The knockout of PUMA results in doubling of the number of primordial follicles in mouse ovaries[81]. Additionally, the knockout of either tumor necrosis factor-alpha or its receptor Fas induces an increase in the primordial follicle pool at birth and a decrease in oocyte apoptosis[82,83]. Therefore, DNA damage-mediated apoptosis is one of the key reasons for the reduced number of mitotic and meiotic processes in germ cells of oogonia.

Based on the data analysis carried out via 10× genomics measurement by Niu and Spradling[50], there are common expression features of apoptosis-related genes in oocytes recovered from 11.5 dpc to 5 dpp mice ovaries according to their time-dependent expression patterns (Fig. 2). In brief, the expression of genes, such as Gsk3b, Mcl1, Smad4, Smad2, Diablo, Birc5, Birc6, Ngf, Nts, Bdnf, and Gdnf, is almost intact in oocytes perinatally, suggesting that the continuous and stable expression of these genes may be attributed to sustained oocyte survival. However, the expression of Bcl2, Gdf9, Bmp15, Tgfb2, Tgfb3, Gata4, Gata6, Tnfsf10, and Igf1 increased gradually, whereas that of Bax, Trp53, Araf, Bad, Bak1, Casp2, Casp8, and Casp9 decreased gradually. Therefore, antiapoptosis genes were upregulated, whereas proapoptotic genes were downregulated simultaneously in the examined oocytes, implying a competitive mechanism within the oocytes that may struggle to survive.

Fig. 2.:
Predicted prosurvival and proapoptotic factors in fetal mice ovary. Bcl2: B-cell lymphoma/leukemia 2; Bmp15: bone morphogenetic protein 15; Casp2: caspase 2; Casp8: caspase 8; Casp9: caspase 9; Gdf9: growth and differentiation factor 9; NTs: neurotrophins.

A cascade of caspase family responses induced by the activation of exogenous BCL apoptotic protein family members, endogenous cytochrome C, and apoptosis-inducing factor has been reported[84]. The number of primordial follicles was intact, although mutations in the proapoptotic factor Bax resulted in more germ line cysts, suggesting a potential link between oocyte apoptosis and cyst breakdown[85–87]. Additionally, knockdown of Caspase2 leads to more primordial follicles[88], whereas antiapoptotic molecules increase the number of primary follicles[89,90]. Overexpression of BCL2 significantly increased the number of primordial follicles perinatally in mice[91]. Moreover, the oocyte apoptosis in Mcl1 depletion mice increases and finally results in POI[60,92,93]. Additionally, the deletion of Bbc3 (BCL2-binding component 3) at 13.5 dpc increased oocyte numbers[94].

An interesting working model was discovered on how progressive apoptosis is driven by the activity of GSK-3β in the oocytes of fetal mice. Under physiological conditions, although the level of GSK-3β protein in oocytes is almost intact from 13.5 dpc to 1 dpp, the gradually decreased activity of GSK-3β modulates the expression level of TP63, tumor protein P63 during MPI by fine-tuning the cytoplasmic-nuclear translocation of β-catenin[16]. TAp63 is a major genomic guardian of the female germ line. This dynamic regulation mechanism could be essential for triggering the DNA damage checking mechanism step-by-step to ensure the highest fidelity of genetic quality in surviving oocytes.

Third, retrotransposons may be active in determining oocyte fate during primordial follicle formation[95,96]. According to Malki et al.[95] and Tharp et al.[96], the non-LTR retrotransposon LINE1 correlated closely with fetal mouse oocyte loss. Briefly, upregulation of L1ORF1p (encoding protein for LINE1) expression resulted in accelerated oocyte depletion and a consequent reduction in ovarian reserve[95]. LINE1 activity triggers oocyte loss in fetal mice through DNA damage-driven apoptosis and the complement system of immunity. In contrast, the reserve of oocytes within the ovary increases whenever the activity of LINE1 is inhibited and the gene checkpoint kinase 2 is deleted[96]. In line with this, caspase 9 (CASP9), the hub of the mitochondrial apoptotic pathway, with its downstream effector caspase 3, was counteracted by endogenous XIAP to regulate the oocyte population during fetal ovarian development. Interestingly, CASP9 deficiency results in increased oocyte accumulation at the pachytene stage, with multiple phosphorylated H2AX foci and high LINE1 expression levels, but with normal levels of synapsis and overall DSB repair. It is possible that oocytes overexpressing LINE1 are preferentially eliminated by CASP9-dependent apoptosis in balance with XIAP during fetal ovarian development[18].

According to existing reports, along with our analysis, antiapoptotic molecules such as BCL2 may protect oocytes from apoptosis, whereas proapoptotic molecules such as p53 induce apoptosis in fetal ovaries. X chromosome self-synapse, GSK-3β/β-catenin system together with CASP9/XIAP systems may be important protective mechanisms that play a crucial role in maintaining the survival of oocytes.

Autophagy-related oocyte loss

Autophagy may be one of the key mechanisms involved in determining the fate of oocytes before and after the primordial follicle formation and may further influence follicle development. Autophagy is a unique cell death pathway and an adaptation to stress that promotes cell survival[97]. It is generally induced when an organism experiences nutrient deficiency, hypoxia, oxidative stress, and inflammatory reactions[98–100]. Inadequate nutrient supply may be one of the main reasons for massive germ cell loss. Starvation treatment for 36 hours in 1.5 dpp and 3 dpp mice resulted in decreased cyst breakdown, together with upregulated levels of autophagy and apoptosis[19], which implies that nutrition supply is necessary for cyst breakdown. Thus, autophagy modulates the formation of primordial follicles and determines the size of the initial pool of primordial follicles established perinatally in mice[101].

Autophagy participates in germ cyst breakdown and primordial follicle assembly by reducing reactive oxygen species (ROS) levels in fetal mouse ovaries[102]. The in vitro culture of 19.5 dpc ovary for 3 days with 3-methyladenine decreases the level of ROS and autophagy and reduces the number of primordial follicles[103]. The ablation of Lhx8 accelerates oocyte autophagy and promotes the protein expression of autophagy-related protein 7, coiled-coil myosin-like BCL2-interacting protein, and microtubule associated protein 1 light chain 3 beta[104]. Additionally, germ cell knockout Atg7 by Tnap-care leads to a decrease in primordial follicle reserve, which suggests that autophagy-related genes, including Atg9a, may be potential pathogenic genes related to POI in women[105]. In addition, Becn1+/− ovaries showed a 56% reduction in germ cells compared with wild-type ovaries at 1 dpp, whereas Atg7−/− ovaries lacked germ cells at this stage[69]. Therefore, autophagy is a survival mechanism of germ cells that maintains the oocyte number supply before germ cyst breakdown and assembly of primordial follicles.

A recent study showed that autophagy actively participates in determining the fate of oocytes in perinatal mice in response to LSD1, a histone-modified demethylase that alters chromosome structure by acting on histone H3-specific lysine residues[106]. The overexpression of Lsd1 in vitro cultured 16.5 dpc mouse ovaries for 3 days resulted in significantly increased primordial follicles. In vivo, a gradual decrease in LSD1 correlated with a significant increase in autophagy-induced oocyte death in perinatal mouse oocytes. The simultaneous inhibition of LSD1 and autophagy rescues oocyte loss by regulating the level of H3K4me2, thus influencing the level of P62. Upon tracking the levels of PCDs in the perinatal ovary under physiological conditions, autophagy may be more important than apoptosis in controlling primordial follicle loss after germ line cyst breakdown[17].

According to previous reports, some autophagy-related proteins are closely correlated with germ cell death (Table 3). Based on the report by Niu and Spradling[50], we found that among all examined time points, the expression of some autophagy-related genes, such as Lsd1, Bcl2, Motor, and Prkag2, were downregulated (Fig. 3), whereas Map1lc3b, Atg101, Bnip3, Hif1a, Ulk1, Atg5, Atg12, Atg3, Atg4a, Atg7, Atg9a, Uvrag, Ulk2, and Sqstm1 was progressively upregulated until primordial follicle formation. These findings agree with those of previous studies[17,100,107]. Collectively, the level of autophagy in the perinatal mouse ovary is influenced by epigenetic mechanisms, possibly involved in determining germ cell fate in the perinatal mouse ovary.

Fig. 3.:
Predicted prosurvival and proautophagy factors in fetal mice ovary.


There has been some interest in discovering how and why oocytes proceed with PCDs since the discovery of conserved oocyte elimination in fetal ovaries in the 1960s[108]. Recent studies have contributed significantly to exploring the possible causes, specific types, and related molecular mechanisms of PCDs in oocytes before ceasing MPI in fetal ovaries. Hence, the fate of oocytes in the fetal ovary seems to be determined by different protective strategies to control the two types of PCDs based on the development of the oocytes and the stage of primordial follicle formation under physiological conditions (Fig. 4). In brief, apoptosis is likely responsible for clearing out oocytes that have failed to accomplish the programmed stage-specific process of meiosis, especially those that failed to repair DSBs. Unlike apoptosis, autophagy focuses on supervising the complement of cytoplasmic development and epigenetic modifications before primordial follicle formation is accomplished. Importantly, the coordination between the two PCDs perinatally determines germ cell fate in mammals.

Fig. 4.:
Schematic of protective mechanisms against apoptosis and autophagy in the fetal oocyte. In the fetal mouse ovary, the dynamic changes in the number of oocytes since mitosis of oogonia are dramatic (red line). The peak number appears before oocyte meiosis initiation around 13.5 dpc. It then continues to decrease throughout fetal development and becomes stable at approximately 3 dpp. PCD including apoptosis (blue line) and autophagy (yellow line) accompany the development of oocytes and may be the major causes of oocyte loss that have been found so far. Both apoptosis and autophagy are active around 17.5 dpc when DSBs in individual oocytes have been thoroughly repaired, and an increasing number of oocytes are arrested at the diplotene stage of meiotic prophase I. According to the present study, the level of autophagy seems to be more vigorous than that of apoptosis. At the same time, at least 3 surveillance mechanisms have been proposed to prevent premature oocyte death during meiosis. From 13.5 dpc, the activity of GSK-3β and the expression of LSD1 decreased gradually along with the processes of oogonia meiosis, germ cyst breakdown, and primordial follicle assembly. As a result, the first protective strategy was developed based on the constant activity of GSK-3β within each oocyte (blue box), from which the level of Tap63 was inhibited and apoptosis was somehow prevented. The second strategy is related to the relatively high level of LSD1 within oocytes during the course (yellow box), which prevents premature autophagy-related death induced by p62 in oocytes. The third strategy focuses on the level of XIAP (green box), which prevents Caspas9-mediated oocyte apoptosis that is possibly induced by LINE1. XIAP prevents oocyte apoptosis through 15.5 dpc to 1 dpp although its expression pattern under physiological conditions is not clear. CASP9: caspase 9; DSBs: double-strand breaks; GSK-3β: glycogen synthase kinase 3 beta; LINE1: long interspersed nuclear element-1; LSD1: lysine-specific demethylase 1; P62: phosphotyrosine-independent ligand for the lck sh2 domain of 62 KDa; also known as SQSTM1, sequestosome-1; PCD: programmed cell death; PGC: primordial germ cell; TAp63: TP63, tumor protein P63; XIAP: X-linked inhibitor of apoptosis.

The major causes of fetal oocyte apoptosis are closely related to the surveillance mechanism that eliminates oocytes with meiotic defects[18,109]. A series of studies have shown that oocytes with either unrepaired DSBs or unsynapsis chromosomes are eliminated by the CHK2-TAp63 apoptotic pathway, which becomes active only after birth[110–114]. Physiologically, fetal oocytes lack TAp63 surveillance before the diplotene stage because the inhibitory effect of high activity of intracytoplasmic GSK3β is turned on during the meiosis progression period, although DSB-induced DNA damage checkpoint signaling, including ATM and CHK2, is active[114]. Coincidentally, the expression peak of TAp63 was synchronized with massive oocyte attrition, which eliminated oocytes with unrepaired DSBs or genetic defects in mice[115]. GSK3β is essential for sustaining fetal oocyte survival by fine-tuning the cytoplasmic-nuclear translocation of β-catenin, which in turn modulates TAp63 expression timely during MPI mice promptly[16].

Meanwhile, the elimination of fetal oocytes could also be a consequence of the concurrent retrotransposon activity or the aforementioned MSCI. According to Tharp et al.[95], the expression and activation of LINE1 elements during epigenetic reprogramming could be detrimental to the viability of MPI fetal oocytes[96]. LINE1 activity triggers oocyte loss in fetal mice through DNA damage-driven apoptosis and the complement system of immunity[96]. Interestingly, Liu et al.[18] found that oocytes overexpressing LINE1 were preferentially eliminated by CASP9-dependent apoptosis in balance with XIAP during fetal ovarian development. Given that retrotransposons in Drosophila exploit a hijacking tactic to robustly propagate in the host genome during oogenesis. Considering this finding, it would be meaningful to determine whether similar mechanisms of retrotransposons are present in mammalian oocyte development[42]. Interestingly, although MSCI-induced apoptosis correlates with fetal oocyte loss, whether the oocyte loss in XO female mice is due to the silencing of the X chromosome that remains unsynapsed requires further research[78].

Multiple studies have shown that autophagy actively participates in a sharp oocyte number decrease, particularly around primordial follicle assembly time[17,19,116,117]. On the one hand, the rare occurrence of apoptotic cells in perinatal ovaries demonstrates that additional PCD mechanisms, such as autophagy, are involved with oocyte attrition before and after birth in the mouse[118]. Further, ultrastructural studies on mammalian oocytes have repeatedly demonstrated the presence of lysosomes and autophagosomes in the studied species[17]. On the other hand, compromised autophagy within the perinatal ovary due to depletion of autophagy-related genes (i.e., Atg7 or Beclin1) results in premature loss of oocytes by 1 dpp in mice, which is similar to POI in humans[69,105]. Coincidentally, our recent study indicates that a stepwise decrease in the levels of LSD1 may be indispensable for the timely control of the degree of oocyte death induced by autophagy in prenatal mice ovaries[17]. Therefore, autophagy appears to be a cell-protective strategy under physiologically relevant conditions to maintain the endowment of oocytes before establishing a primordial follicle pool[69].

The quality control of oocytes is key to explain why at least two types of PCDs have been employed to determine cell fate. Briefly, studies have shown that apoptosis corresponds to DNA damage failure induced by unsuccessful meiosis or retrotransposons[16,95,96]. Alternatively, more severe oocyte death induced by autophagy may result from programmed epigenetic modification mechanisms[33]. Interestingly, autophagy-induced PCD in oocytes does not affect meiosis because the number of oocytes recovered after inhibiting autophagy was significantly higher than that recovered after apoptosis[18,103,118]. The burst of autophagy may be an adaptive response to nutritional stress once the newborn is deprived of placental nutrients[119]. Autophagy also participates in cyst breakdown and primordial follicle assembly by reducing ROS levels in fetal mouse ovaries[102].

The relationship between apoptosis and autophagy is complex. In some cases, autophagy inhibits apoptosis, a cell survival pathway. In other cases, autophagy itself induces cell death or acts in conjunction with apoptosis, possibly acting as a backup mechanism to induce cell death in the absence of apoptosis. Although the exact mechanisms upon the crosstalk between apoptosis and autophagy have been established remain unclear, several intermediate molecules have been identified and discussed. For example, P62, Beclin1, Bcl-2/Bcl-xL, autophagy-related genes, and autophagic degradation of caspases are likely critical players in regulating and being regulated by pro- and antiapoptotic molecules[120]. In conclusion, in fetal mouse ovaries, apoptosis appears to eliminate oocytes with genetic or meiotic pairing errors, whereas autophagy helps oocytes to form functional follicles using well-prepared oocytes, although both are important for oocyte PCD.

In summary, this study demonstrates that both apoptosis and autophagy are involved in determining oocyte fate in fetal ovaries. Although the endogenous and exogenous factors cause the two typical PCDs in oocytes to remain elusive, the oocytes have developed mature protective mechanisms before MPI has been successfully achieved, including the progressively controlled activity of GSK3β, the levels of LSD1, and the balanced relationship between XIAP and CASP9, to prevent premature oocyte loss. Overall, programmed oocyte death in fetal ovaries represents a stringent oocyte quality control mechanism, which ensures that highly qualified oocytes at MPI are endowed with the opportunity to form primordial follicles.



Author contributions

J.Z. contributed to literature retrieval and drafted the manuscript. W.W. participated in the drafting of Figures 2 and 3. G.X. provided suggestions for the structure of this review. C.W. contributed by providing instructions and reviewing the manuscript.


This study was supported by grants from the National Key Research & Developmental Program of China (2018YFC1003701, 2018YFC1003801), Natural Science Foundation of China (31872792, 32071132, 32070839), Institution of Higher Education Projects of Building First-class Discipline Construction in Ningxia Region (Biology) (NXYLXK2017B05), and Project of State Key Laboratory of Agrobiotechnology (2015SKLAB4-1).

Conflicts of interest

All authors declare no conflict of interest.


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Oocyte; Primordial follicle formation; Protective mechanism; Apoptosis; Autophagy

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