Retinoic Acid Signalling and the Control of Meiotic Entry in the Human Fetal Gonad

Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
PLoS ONE (Impact Factor: 3.53). 06/2011; 6(6):e20249. DOI: 10.1371/journal.pone.0020249
Source: PubMed

ABSTRACT The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in regulating the onset of meiosis in the human fetal ovary, mechanisms other than CYP26B1-mediated metabolism of RA may exist to inhibit the entry of germ cells into meiosis in the human fetal testis.

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Available from: Philippa T K Saunders, Jul 28, 2015
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    • "Simultaneously they acquire the ability to initiate sexual differentiation and enter meiosis, as evidenced through DAZL expression (Anderson et al., 2007; Lin et al., 2008). The expression of the meiosis gatekeeper STRA8 can be detected shortly thereafter (Le Bouffant et al., 2010; Childs et al., 2011). "
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    ABSTRACT: We identified three doublesex and mab-3-related transcription factors (DMRT) that were sexually differentially expressed in human fetal gonads and present in the ovaries at the time of meiotic initiation. These were also identified in murine embryonic female germ cells. Among these, we focused on DMRTA2 (DMRT5), whose function is unknown in the developing gonads, and clarified its role in human female fetal germ cells, using an original xenograft model. Early human fetal ovaries (8 to 11 weeks post- fertilization) were grafted into nude mice. Grafted ovaries developed normally, with no apparent overt changes, when compared to ungrafted ovaries at equivalent developmental stages. Appropriate germ cell density, mitotic /meiotic transition, markers of meiotic progression and follicle formation were evident. Four weeks after grafting, mice were treated with siRNA, specifically targeting human DMRTA2 mRNA. DMRTA2 inhibition triggered an increase in undifferentiated FUT4-positive germ cells and a decrease in the percentage of meiotic γH2AX-positive germ cells, when compared with mice that were injected with control siRNA. Interestingly, the expression of markers associated with pre-meiotic germ cell differentiation was also impaired, as was the expression of DMRTB1 (DMRT6) and DMRTC2 (DMRT7). This study reveals, for the first time, the requirement of DMRTA2 for normal human female embryonic germ cell development. DMRTA2 appears to be necessary for proper differentiation of oogonia, prior to entry into meiosis, in the human species. Additionally, we developed a new model of organ xenografting, coupled with RNA interference, which provides a useful tool for genetic investigations of human germline development.
    Molecular Human Reproduction 07/2014; 20(10). DOI:10.1093/molehr/gau058 · 3.48 Impact Factor
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    • "The retinoic acid metabolizing enzyme CYP21B protects germ cells in the testes (Griswold et al., 2011). This model has been clearly elucidated in the mouse, and while the key aspects of this mechanism are likely to be conserved in the human there are also some differences, exemplified by the high level of CYP21B expression in the fetal ovary as well as the testis (Le Bouffant et al., 2010; Childs et al., 2011). There are few studies describing human ovarian development in later gestation: it is believed that primordial follicle formation is essentially complete before birth with any remaining oogonia (not within primordial follicles) being removed in the first years of life (Byskov et al., 2011). "
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    ABSTRACT: BACKGROUND Advanced maternal age is associated with reduced fertility and adverse pregnancy outcomes. This review details recent developments in our understanding of the biology and mechanisms underlying reproductive ageing in women and the implications for fertility and pregnancy.METHODS Sociological online libraries (IBSS, SocINDEX), PubMed and Google Scholar were searched for relevant demographic, epidemiological, clinical and biological studies, using key words and hierarchical MeSH terms. From this, we identified and focused on key topics where it was judged that there had been clinically relevant advances in the understanding of ovarian and uterine ageing with implications for improved diagnostics and novel interventions.RESULTSMapping of the ovarian reserve, follicular dynamics and associated biomarkers, across the reproductive lifespan has recently been performed. This now allows an assessment of the effects of environmental, lifestyle and prenatal exposures on follicular dynamics and the identification of their impact during periods of germ cell vulnerability and may also facilitate early identification of individuals with shorter reproductive lifespans. If women choose to time their family based on their ovarian reserve this would redefine the meaning of family planning. Despite recent reports of the potential existence of stem cells which may be used to restore the primordial follicle and thereby the oocyte pool, therapeutic interventions in female reproductive ageing at present remain limited. Maternal ageing has detrimental effects on decidual and placental development, which may be related to repeated exposure to sex steroids and underlie the association of ageing with adverse perinatal outcomes.CONCLUSIONS Ageing has incontrovertible detrimental effects on the ovary and the uterus. Our enhanced understanding of ovarian ageing will facilitate early identification of individuals at greatest risk, and novel therapeutic interventions. Changes in both ovary and uterus are in addition to age-related co-morbidities, which together have synergistic effects on reducing the probability of a successful pregnancy outcome.
    Human Reproduction Update 10/2012; 19(1). DOI:10.1093/humupd/dms043 · 8.66 Impact Factor
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    ABSTRACT: Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY gene. Recent genetic and transcriptomic studies challenge this view and show that two master pathways simultaneously repress male-specific genes and activate female-specific genetic cascades. This antagonistic action is maintained from embryonic stages to adulthood. The differentiation of the ovarian somatic component is regulated by both the forkhead transcription factor FOXL2 (alone or in combination with oestrogens according to the species) and β-catenin pathway activated by Wnt4 and Rspo1. The sex-specific change in the fate of primordial germ cells depends on the gonad environment. Female gonocytes actively proliferate by mitosis then enter meiosis I until the diplotene stage. Primordial follicle formation occurs when oocytes are individually surrounded with pre-granulosa cells. In mammals, the population of primordial follicles serves as a resting and finite pool of oocytes available during the female reproductive life span. Recent data on factors controlling these molecular processes will be presented in this review.
    01/2011; 205(4):201-21. DOI:10.1051/jbio/2011021
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