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Inactivation of Exosc10 in the oocyte impairs oocyte development and maturation, leading to a depletion of the ovarian reserve in mice.

ABSTRACT: EXOSC10 is a catalytic subunit of the nuclear RNA exosome, and possesses a 3'-5' exoribonuclease activity. The enzyme processes and degrades different classes of RNAs. To delineate the role of EXOSC10 during oocyte growth, specific Exosc10 inactivation was performed in oocytes from the primordial follicle stage onward using the Gdf9-iCre; Exosc10 ^f/- mouse model (Exosc10 ^cKO(Gdf9)). Exosc10 ^cKO(Gdf9) female mice are infertile. The onset of puberty and the estrus cycle in mutants are initially normal and ovaries contain all follicle classes. By the age of eight weeks, vaginal smears reveal irregular estrus cycles and mutant ovaries are completely depleted of follicles. Mutant oocytes retrieved from the oviduct are degenerated, and occasionally show an enlarged polar body, which may reflect a defective first meiotic division. Under fertilization conditions, the mutant oocytes do not enter into an embryonic development process. Furthermore, we conducted a comparative proteome analysis of wild type and Exosc10 knockout mouse ovaries, and identified EXOSC10-dependent proteins involved in many biological processes, such as meiotic cell cycle progression and oocyte maturation. Our results unambiguously demonstrate an essential role for EXOSC10 in oogenesis and may serve as a model for primary ovarian insufficiency in humans. Data are available via ProteomeXchange with identifier PXD039417.

SUBMITTER: Demini L

PROVIDER: S-EPMC10008699 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Inactivation of Exosc10 in the oocyte impairs oocyte development and maturation, leading to a depletion of the ovarian reserve in mice.

Demini Leïla L Kervarrec Christine C Guillot Laëtitia L Com Emmanuelle E Lavigne Régis R Kernanec Pierre-Yves PY Primig Michael M Pineau Charles C Petit Fabrice G FG Jamin Soazik P SP

International journal of biological sciences 20230131 4

EXOSC10 is a catalytic subunit of the nuclear RNA exosome, and possesses a 3'-5' exoribonuclease activity. The enzyme processes and degrades different classes of RNAs. To delineate the role of EXOSC10 during oocyte growth, specific Exosc10 inactivation was performed in oocytes from the primordial follicle stage onward using the Gdf9-iCre; Exosc10 f/- mouse model (Exosc10 cKO(Gdf9)). Exosc10 cKO(Gdf9) female mice are infertile. T ...[more]

PMID: 36923944

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Project description:BackgroundAn estimated 1 in 350 women carry germline BRCA1/2 mutations, which confer an increased risk of developing breast and ovarian cancer, and may also contribute to subfertility. All mature, sex steroid-producing ovarian follicles are drawn from the pool of non-renewable primordial follicles, termed the 'ovarian reserve'. The clinical implications of early ovarian reserve exhaustion extend beyond infertility, to include the long-term adverse health consequences of loss of endocrine function and premature menopause. We aimed to determine whether conditional loss of Brca1 in oocytes impacts ovarian follicle numbers, oocyte quality and fertility in mice with advancing maternal age. We also aimed to determine the utility of AMH as a marker of ovarian function, by assessing circulating AMH levels in mice and women with BRCA1/2 mutations, and correlating this with ovarian follicle counts.MethodsIn this study, we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. To recapitulate loss of BRCA1 protein function in oocytes, we generated mice with conditional gene deletion of Brca1 in oocytes using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+).FindingsWhile the length of the fertile lifespan was not altered between groups after a comprehensive breeding trial, conditional loss of Brca1 in oocytes led to reduced litter size in female mice. Brca1 cKO animals had a reduced ovarian reserve and oocyte maturation was impaired with advanced maternal age at postnatal day (PN)300, compared to WT animals. Serum anti-Müllerian hormone (AMH) concentrations (the gold-standard indirect marker of the ovarian reserve used in clinical practice) were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from a small cohort of premenopausal women with BRCA1/2 mutations.InterpretationTogether, our data demonstrate that BRCA1 is a key regulator of oocyte number and quality in females and suggest that caution should be used in relying on AMH as a reliable marker of the ovarian reserve in this context.FundingThis work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the Australian Research Council (ALW - DE21010037 and KJH - FT190100265), as well as the National Breast Cancer Foundation (IIRS-22-092) awarded to ALW and KJH. LRA, YML, LT, EOKS and MG were supported by Australian Government Research Training Program Scholarships. LRA, YML and LT were also supported by a Monash Graduate Excellence Scholarship. YC, SG and XC were supported by Monash Biomedicine Discovery Institute PhD Scholarships. LRA was also supported by a Monash University ECPF24-6809920940 Fellowship. JMS was supported by NHMRC funding (2011299). MH was supported by an NHMRC Investigator Grant (1193838).

Project description:Study objectiveThe impairment of the ovarian response in in vitro fertilization (IVF) cycles after salpingectomy remains contentious. Therefore, we investigated whether a history of salpingectomy affects the number of oocytes retrieved in women undergoing IVF in comparison with the number in women without underlying tubal disease.DesignCase-control study (Canadian Task Force Classification II-2).SettingA tertiary hospital-affiliated fertility center.PatientsFifty-four women aged <35 years with a history of salpingectomy and 59 age-matched women without tubal disease.InterventionsGonadotropin-releasing hormone antagonist protocol for controlled ovarian stimulation and transvaginal oocyte retrieval.Measurements and main resultsThe antral follicle count (AFC), anti-Müllerian hormone (AMH) levels, and the number of retrieved oocytes were significantly lower in women with prior salpingectomy than in women without tubal disease. Day-3 follicle-stimulating hormone (FSH) levels, total gonadotropin dosage, and stimulation days did not significantly differ between the groups. The indications of salpingectomy (i.e., hydrosalpinx and ectopic pregnancy) did not differ significantly in terms of ovarian response or reserve among women with salpingectomy history. A history of salpingectomy and other factors related to ovarian response in IVF, such as age, AMH, AFC, day-3 FSH, and total gonadotropin dose, were significantly correlated with the number of oocytes retrieved by univariate regression analysis. In the multivariate-adjusted model after controlling all the above-mentioned variables, only AFC and AMH levels continued to exhibit significant associations with the number of retrieved oocytes. In a subgroup analysis, the negative impact of prior salpingectomy on the number of retrieved oocytes was especially significant in women with suboptimal ovarian reserves (defined as AMH < 4 ng/mL), regardless of the indication of salpingectomy or whether salpingectomy was bilateral or unilateral.ConclusionA negative effect on the number of retrieved oocytes in the subsequent IVF cycle after salpingectomy is more likely in women aged <35 years with suboptimal ovarian reserve. Nevertheless, postsurgical AMH and AFC levels still possess a more direct predictive value on ovarian response than the history of salpingectomy.

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Inactivation of Exosc10 in the oocyte impairs oocyte development and maturation, leading to a depletion of the ovarian reserve in mice.

Publications

Inactivation of <i>Exosc10</i> in the oocyte impairs oocyte development and maturation, leading to a depletion of the ovarian reserve in mice.

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