Chromosome Errors in Human Eggs Shape Natural Fertility Over Reproductive Life Span

Gruhn, Jennifer R.; Zielinska, Agata P; Shukla, Vallari; Blanshard, Robert; Capalbo, Antonio; Cimadomo, Danilo; Nikiforov, Dmitry; Chan, Andrew C.; Newnham, Louise; Vogel, Ivan; Scarica, Catello; Krapchev, Marta; Taylor, Deborah M.; Kristensen, Stine Gry; Cheng, Jin; Ernst, Erik; Bjørn, Anne-Mette Bay; Colmorn, Lotte Berdiin; Blayney, Martyn; Elder, Kay; Liss, Joanna; Hartshorne, Geraldine M.; Grøndahl, Marie Louise; Rienzi, Laura; Ubaldi, Filippo Maria; Łukaszuk, Krzysztof; Andersen, Claus Yding; Schuh, Melina; Hoffmann, Eva R.

doi:10.1097/ogx.0000000000000817

Cited by 49 publications

(93 citation statements)

References 23 publications

(29 reference statements)

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“…Three different abnormal segregation patterns have been found to contribute to the high rate of human aneuploidy: premature separation of sister chromatids (PSSC), 18 reverse segregation (RS), 2 and meiosis I non-disjunction (MI NDJ). 19 In a recent study by Gruhn et al, 1…”

Section: The U-curve Of Aneuploidy and Types Of Meiotic Segregationmentioning

confidence: 93%

“…More recently, oocytes obtained during ovarian tissue cryopreservation have also been developed as an ex vivo source. 1,13 The large number of oocytes obtained from different sources have enabled broad conclusions to be reached, including that errors in chromosome segregation resulting in aneuploidy is a general feature of human oocytes and preimplantation embryos. Whereas aneuploidies are highly affected by maternal age, segregation errors during embryonic divisions are independent of maternal age factors.…”

Section: Introductionmentioning

confidence: 99%

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Origins and mechanisms leading to aneuploidy in human eggs

et al. 2021

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The gain or loss of a chromosome-or aneuploidy-acts as one of the major triggers for infertility and pregnancy loss in humans. These chromosomal abnormalities affect more than 40% of eggs in women at both ends of the age spectrum, that is, young girls as well as women of advancing maternal age. Recent studies in human oocytes and embryos using genomics, cytogenetics, and in silico modeling all provide new insight into the rates and potential genetic and cellular factors associated with aneuploidy at varying stages of development. Here, we review recent studies that are shedding light on potential molecular mechanisms of chromosome missegregation in oocytes and embryos across the entire female reproductive life span.

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Section: The U-curve Of Aneuploidy and Types Of Meiotic Segregationmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Origins and mechanisms leading to aneuploidy in human eggs

et al. 2021

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“…Deciphering how this process is orchestrated and more specifically how forces are transmitted from the cortex to the spindle is of significant public health interest, as Development • Accepted manuscript defects in force transmission could trigger chromosome misalignment and subsequent egg aneuploidy (Bennabi et al, 2020), the main cause of female infertility (Gruhn et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Myosin-X is dispensable for spindle morphogenesis and positioning in the mouse oocyte

et al. 2021

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Off-center spindle positioning in mammalian oocytes enables asymmetric divisions in size, important for subsequent embryogenesis. The migration of the meiosis I spindle from the oocyte center to its cortex is mediated by F-actin. Specifically, an F-actin-cage surrounds the microtubule spindle and applies forces to it. To better understand how F-actin transmits forces to the spindle, we studied a potential direct link between F-actin and microtubules. For this, we tested the implication of Myosin-X, a known F-actin and microtubule binder involved in spindle morphogenesis and/or positioning in somatic cells, amphibian oocytes and embryos. Using a mouse strain conditionally invalidated for Myosin-X in oocytes and by live cell imaging, we show that Myosin-X is not localized on the spindle and dispensable for spindle and F-actin assembly. It is not required for force transmission since spindle migration and chromosome alignment occur normally. More broadly, Myosin-X is dispensable for oocyte developmental potential and female fertility. We therefore exclude a role for Myosin-X in transmitting F-actin-mediated forces to the spindle, opening new perspectives regarding this mechanism in mouse oocytes, which differs from most mitotic cells.

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“…First, homologous chromosomes are separated during meiosis I (MI), followed by sister chromatid separation in meiosis II (MII). Errors in MI give rise to aneuploid gametes that, if fertilized, lead to congenital birth defects or embryo development failure [1][2][3]. Critical to accurate chromosome segregation is the formation of a bipolar spindle apparatus which captures chromosomes and pulls them apart.…”

Section: Introductionmentioning

confidence: 99%

Aurora kinase A is essential for meiosis in mouse oocytes

Blengini

Ibrahimian

Vaškovičová

et al. 2021

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The Aurora protein kinases are well-established regulators of spindle building and chromosome segregation in mitotic and meiotic cells. In mouse oocytes, there is significant Aurora kinase A (AURKA) compensatory abilities when the other Aurora kinase homologs are deleted. Whether the other homologs, AURKB or AURKC can compensate for loss of AURKA is not known. Using a conditional mouse oocyte knockout model, we demonstrate that this compensation is not reciprocal because female oocyte-specific knockout mice are sterile and their oocytes fail to complete meiosis I. In determining the AURKA-specific functions, we demonstrate that its first meiotic requirement is to activate Polo-like kinase 1 at microtubule organizing centers (MTOCs; meiotic spindle poles). This activation induces fragmentation of the MTOCs, a step essential for building a bipolar spindle. The next step that requires AURKA is building the liquid-like spindle domain that involves TACC3. Finally, we find that AURKA is also required for anaphase I onset to trigger cohesin cleavage in an APC/C independent manner. We conclude that AURKA has multiple functions essential to completing MI that are distinct from AURKB and AURKC.Author SummaryFemale gametes, oocytes, are uniquely prone to chromosome segregation errors in meiosis I that are associated with early miscarriages. The Aurora protein kinases are essential to control chromosome segregation in all cell types. During mitosis, Aurora kinase A (AURKA) regulates the building of the spindle, the machinery responsible for pulling chromosomes apart. Here, we use a genetic approach to demonstrate that AURKA is essential for meiosis I in mouse oocytes. AURKA is required at multiple steps in meiosis I, first to trigger fragmentation of protein structures that make up the two ends of the meiotic spindle, later to regulate building of a specialized phase-separated spindle domain, and finally to trigger efficient cleavage of cohesin, the molecular glue that holds chromosomes together until anaphase onset. These findings are the first demonstration of distinct Aurora kinase function that cannot be compensated for by the other two homologs. Therefore, this mouse model is excellent tool for pinpointing specific Aurora kinase functions and identifying AURKA target proteins critical for chromosome segregation in meiosis I.

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Chromosome Errors in Human Eggs Shape Natural Fertility Over Reproductive Life Span

Abstract: Data availability: All data are available at dbGaP (study #35769) under appropriate Data Use Certification (DUC) agreement in accordance with Danish ethical regulation and General Data Protection Regulation (GDPR).

Cited by 49 publications

References 23 publications

Origins and mechanisms leading to aneuploidy in human eggs

Origins and mechanisms leading to aneuploidy in human eggs

Myosin-X is dispensable for spindle morphogenesis and positioning in the mouse oocyte

Aurora kinase A is essential for meiosis in mouse oocytes

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