Abstract
In all mammalian species studied, a marked oocyte loss occurs during the fetal life before their enclosure within the primordial follicle. The concept that female mammals are born with all of the oocytes they will ever posses and the consequent notion that the age-related ovarian failure and menopause occur when the oocyte ovarian reserve is exhausted, render particular relevant to understand the reasons and the mechanisms of oocyte demise in the fetal ovary. Over the years, three main hypotheses to explain the cause of fetal oocyte death have been proposed: (1) the number of oocytes formed in the ovary is in excess respect to the supporting cell, (2) the process of cross over central in prophase I, requires critical molecular processes subjected to frequent errors leading to oocyte death and (3) most oocytes could sacrify themselves donating their cytoplasm content to a subset of surviving oocytes. Mainly during the last three decades, researchers have reported evidence favoring each of these hypotheses; thus suggesting that the survival or death of fetal oocytes depends on several conditions and mechanisms. The concept that cell death is a carefully controlled process both at genomic and molecular level termed apoptosis or programmed cell death (PCD) affirming at the beginning of 80 years, stimulated researchers to analyze in more details the morphological and molecular characteristics as well as the kinetics of the fetal oocyte elimination. In the next sections of the present chapter, we will critically review the principal studies carried out, mainly in the mouse, in our and other laboratories that are slowly disclosing the complexity of the fetal oocyte elimination.
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Albamonte MS, Willis MA, Albamonte MI et al (2008) The developing human ovary: immunohistochemical analysis of germ-cell-specific VASA protein, BCL-2/BAX expression balance and apoptosis. Hum Reprod 23:1895–1901
Alton M, Taketo T (2007) Switch from BAX-dependent to BAX-independent germ cell loss during the development of fetal mouse ovaries. J Cell Sci 120:417–424
Anderson RA, Robinson LL, Brooks J et al (2002) Neurotropins and their receptors are expressed in the human fetal ovary. J Clin Endocrinol Metab 87:890–897
Baker TG (1963) A quantitative and cytological study of germ cells in human ovaries. Proc Roy Soc London Ser B 158:417–433
Bakken AH, McClanahan M (1978) Patterns of RNA synthesis in early meiotic prophase oocytes from fetal mouse ovaries. Chromosoma 67:21–40
Beaumont HM, Mandl AM (1961) A quantitative and cytological study of oogonia and oocytes in the fetal and neonatal rat. Proc R Soc London (B) 155:557–579
Bergeron L, Perez GI, Macdonald G et al (1998) Defects in regulation of apoptosis in caspase-2 deficient mice. Genes Dev 12:1304–1314
Borum K (1961) Oogenesis in the mouse: a study of the meiotic prophase. Exp Cell Res 24:2495–2507
Burgoyne PS, Baker TG (1985) Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J Reprod Fertil 75:633–645
Castedo M, Ferri KF, Kroemer G (2002) Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ 9:99–100
Coucouvanis EC, Sherwood SW, Carswell-Crumpton C et al (1993) Evidence that the mechanism of prenatal germ cell death in the mouse is apoptosis. Exp Cell Res 209:238–247
Daugas E, Susin SA, Zamzami N et al (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14:729–739
De Felici M (2000) Regulation of primordial germ cell development in the mouse. Int J Dev Biol 44:575–580
De Felici M, Di Carlo A, Pesce M et al (1999) Bcl-2 and Bax regulation of apoptosis in germ cells during prenatal oogenesis in the mouse embryo. Cell Death Differ 6:908–915
De Felici M, Lobascio AM, Klinger FG (2008) Cell death in fetal oocytes: many players for multiple pathways. Autophagy 4:240–242
de Vries S, Baart EB, Dekker M et al (1999) Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Gene Dev 13:523–531
Doneda L, Klinger FG, Larizza L et al (2002) KL/KIT co-expression in mouse fetal oocytes. Int J Dev Biol 46:1015–1021
Faddy MJ, Gosden RG, Gougeon A et al (1992) Accelerated disappearance of ovarian follicles in mid-life: implication for forecasting menopause. Hum Reprod 7:1342–1346
Flaws JA, Hirshfield AN, Hewitt JA et al (2001) Effect of Bcl-2 on the primordial follicle endowment in the mouse ovary. Biol Reprod 64:1153–1159
Forabosco A, Sforza C, De Pol A et al (1991) Morphometric study of the human neonatal ovary. Anat Rec 231:201–208
Garcia-Cruz R, Roig I, Robles P et al (2009) ATR, BRCA1 and gammaH2AX localize to unsynapsed chromosomes at the pachytene stage in human oocytes. Reprod Biomed Online 18:37–44
Ghafari F, Gutierrez CG, Hartshorne GM (2007a) Apoptosis in mouse fetal and neonatal oocytes during meiotic prophase one. BMC Dev Biol 7:87. doi:10.1186/1471-213X-7-87
Gondos B (1978) Oogonia and oocytes in mammals. In: Jones RE (ed) The vertebrate ovary. Plenum, NY
Greenfeld CR, Pepling ME, Babus JK et al (2007) BAX regulates follicular endowment in mice. Reproduction 133:865–876
Guo M, Sato E, Li X et al (2002) Induction of apoptosis mediated by fas receptor and activation of caspase-3 in MRL-+/+ or MRL-lpr/lpr murine oocytes. Zygote 10:17–22
Hansen KR, Knowlton NS, Thyer AC et al (2008) A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 23:699–708
Harada H, Andersen JS, Mann M et al (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A 98:9666–9970
Hartshorne GM, Lyrakou S, Hamoda H et al (2009) Oogenesis and cell death in human prenatal ovaries: what are the criteria for oocyte selection? Mol Hum Reprod 15:805–819
Jin X, Han CS, Yu FQ et al (2005) Anti-apoptotic action of stem cell factor on oocytes in primordial follicles and its signal transduction. Mol Reprod Dev 70:82–90
Kasai S, Chuma S, Motoyama N et al (2003) Haploinsufficiency of Bcl-x leads to male-specific defects in fetal germ cells: differential regulation of germ cell apoptosis between the sexes. Dev Biol 264:202–216
Kennedy SG, Wagner AJ, Conzen SD et al (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11:701–13
Keeney S, Neale MJ (2006) Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation. Biochem Soc Trans 34:523–5
Klinger FG (2002) Cell cycle control during embryonic gametogenesis and mechanisms of apoptotic regulation in murine fetal oocytes. PhD Thesis
Klinger FG, De Felici M (2002) In vitro development of mouse growing oocytes from fetal oocytes: stage-specific regulation by stem cell factor and granulosa cells. Dev Biol 244:85–95
Kroemer G, Galluzzi L, Vandenabeele P et al (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16:3–11
Liu CF, Parker K, Yao HH (2010) WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary. PLoS One 5(4):e10382
Lobascio AM, Klinger FG, De Felici M (2007a) Isolation of apoptotic mouse fetal oocytes by Annexin V assay. Int J Dev Biol 51:157–60
Lobascio AM, Klinger FG, Scaldaferri ML et al (2007b) Analysis of programmed cell death in mouse fetal oocytes. Reproduction 134:241–252
Lyrakou S, Hultén MA, Hartshorne GM (2002) Growth factors promote meiosis in mouse fetal ovaries in vitro. Mol Hum Reprod 8:906–911
Manova K, Nocka K, Besmer P et al (1990) Gonadal expression of c-kit encoded at the W locus of the mouse. Development 110:1057–1069
Matikainen T, Perez GI, Zheng TS et al (2001) Caspase 3 gene knockout defines cell lineage specificity for programmed cell death signalling in the ovary. Endocrinology 142:2468–2480
Maurer U, Charvet C, Wagman AS et al (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21:749–60
Modi DN, Sane S, Bhartiya D (2003) Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads. Mol Hum Reprod 9:219–225
Morita Y, Manganaro TF, Tao XJ et al (1999) Requirement for phosphatidylinositol-3’-kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse. Endocrinology 140:941–949
Morita Y, Maravei DV, Bergeron L et al (2001) Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function. Cell Death Differ 8:614–620
Morrison LJ, Marcinkiewicz JL (2002) Tumor necrosis factor alpha enhances oocyte/follicle apoptosis in the neonatal rat ovary. Biol Reprod 66:450–457
Nichols SM, Bavister BD, Brenner CA et al (2005) Ovarian senescence in the rhesus monkey (Macaca mulatta). Hum Reprod 20:79–83
Paredes A, Romero C, Dissen GA et al (2004) TrkB receptors are required for follicular growth and oocyte survival in the mammalian ovary. Dev Biol 15:430–439
Pelzel HR, Schlamp CL, Nickells RW (2010) Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neurosci 11:62. doi:10.1186/1471-2202-11-62
Pepling ME, Spradling AC (2001) Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicols. Dev Biol 234:339–351
Perez GI, Robles R, Knudson CM et al (1999) Prolongation of ovarian life span into advanced chronological age by Bax-deficient. Nat Genet 21:200–203
Pesce M, Farrace MG, Piacentini M et al (1993) Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 118:1089–1094
Pesce M, Farrace MG, Amendola A et al (1997) In: Tilly JL, Strauss JF III, Tenniswood M (eds) Cell Death in Reproductive Physiology. Springer, New York
Ratts VS, Flaws JA, Kolp R et al (1995) Ablation of Bcl-2 gene expression decreases the number of oocytes and primordial follicles established in the post-natal female mouse gonad. Endocrinology 136:3665–3668
Reddy P, Shen L, Ren C et al (2005) Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development. Dev Biol 281:160–170
Rodrigues P, Limback D, McGinnis LK et al (2009) Multiple mechanisms of germ cell loss in the perinatal mouse ovary. Reproduction 137:709–720
Rucker EB, Dierisseau P, Wagner KU et al (2000) Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis. Mol Endocrinol 14:1038–1052
Sakata S, Sakamaki K, Watanabe K et al (2003) Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice. Cell Death Differ 10:676–686
Slee EA, Harte MT, Kluck RM et al (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144:281–292
Songyang Z, Baltimore D, Cantley LC et al (1997) Interleukin 3-dependent survival by the Akt protein kinase. Proc Natl Acad Sci USA 94:11345–11350
Spears N, Molinek MD, Robinson LL et al (2003) The role of neurotrophin receptors in female germ-cell survival in mouse and human. Development 130:5481–5491
Tam PP, Snow MH (1981) Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 64:133–147
Tease C, Hartshorne G, Hultén M (2006) Altered patterns of meiotic recombination in human fetal oocytes with asynapsis and/or synaptonemal complex fragmentation at pachytene. Reprod Biomed Online 13:88–95
Thomson TC, Johnson J (2010) Inducible somatic oocyte destruction in response to rapamycin requires wild-type regulation of follicle cell epithelial polarity. Cell Death Differ. doi:doi:10.1038/cdd.2010.49
Tingen C, Kim A, Woodruff TK (2009) The primordial pool of follicles and nest breakdown in mammalian ovaries. Mol Hum Reprod 15:795–803
Turner JM, Mahadevaiah SK, Fernandez-Capetillo O et al (2005) Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37:41–47
Vaskivuo TE, Anttonen M, Herva R et al (2001) Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4. J Clin Endocrinol Metab 86:3421–3429
Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442
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Klinger, F.G., De Felici, M. (2011). Programmed Cell Death in Fetal Oocytes. In: Cell Death in Mammalian Ovary. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1134-1_8
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DOI: https://doi.org/10.1007/978-94-007-1134-1_8
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