Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices

Cell, Journal Year: 2023, Volume and Issue: 186(24), P. 5308 - 5327.e25

Published: Nov. 1, 2023

Mammalian oocytes are filled with poorly understood structures called cytoplasmic lattices. First discovered in the 1960s and speculated to correspond mammalian yolk, ribosomal arrays, or intermediate filaments, their function has remained enigmatic date. Here, we show that lattices sites where store essential proteins for early embryonic development. Using super-resolution light microscopy cryoelectron tomography, composed of filaments a high surface area, which contain PADI6 subcortical maternal complex proteins. The associate many critical development, including control epigenetic reprogramming preimplantation embryo. Loss by knocking out prevents accumulation these results arrest. Our work suggests enrich maternally provided prevent premature degradation cellular activity, thereby enabling

Language: Английский

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The subcortical maternal complex: emerging roles and novel perspectives

Molecular Human Reproduction, Journal Year: 2021, Volume and Issue: 27(7)

Published: June 29, 2021

Abstract Since its recent discovery, the subcortical maternal complex (SCMC) is emerging as a maternally inherited and crucial biological structure for initial stages of embryogenesis in mammals. Uniquely expressed oocytes preimplantation embryos, where it localizes to cell subcortex, this multiprotein essential early embryo development mouse functionally conserved across mammalian species, including humans. The has been linked key processes leading transition from oocyte embryo, meiotic spindle formation positioning, regulation translation, organelle redistribution, epigenetic reprogramming. Yet, underlying molecular mechanisms these diverse functions are just beginning be understood, hindered by unresolved interplay SCMC components variations lethal phenotypes. Here we review advances confirming involvement human infertility, revealing an unexpected relationship with offspring health. Moreover, organization being further revealed terms novel interactions additional constituents. Collectively, evidence prompts new avenues investigation into possible roles during process oogenesis transcript turnover transition.

Language: Английский

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Epigenetics of pregnancy: looking beyond the DNA code

Journal of Assisted Reproduction and Genetics, Journal Year: 2022, Volume and Issue: 39(4), P. 801 - 816

Published: March 17, 2022

Abstract Epigenetics is the branch of genetics that studies different mechanisms influence gene expression without direct modification DNA sequence. An ever-increasing amount evidence suggests such regulatory processes may play a pivotal role both in initiation pregnancy and later embryonic fetal development, thus determining long-term effects even adult life. In this narrative review, we summarize current knowledge on epigenetics pregnancy, from its most studied well-known to new frontiers epigenetic regulation, as ncRNAs gestational environment brain development. Epigenetic are dynamic phenomenon responds maternal–fetal environmental factors, which can modify embryo-fetal development during various phases. Therefore, also recapitulate notable factors affect prenatal maternal nutrition, stress hormones, microbiome, teratogens, focusing their ability cause modifications ultimately fetus. Despite promising advancements more experience data topic still needed. A better understanding regulation could fact prove valuable towards management physiological pregnancies assisted reproduction treatments, other than allowing comprehend origin multifactorial pathological conditions neurodevelopmental disorders.

Language: Английский

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Imprinting disorders

Nature Reviews Disease Primers, Journal Year: 2023, Volume and Issue: 9(1)

Published: June 29, 2023

Language: Английский

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Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review

Human Reproduction Update, Journal Year: 2023, Volume and Issue: 30(1), P. 48 - 80

Published: Sept. 27, 2023

Abstract BACKGROUND Infertility and pregnancy loss are longstanding problems. Successful fertilization high-quality embryos prerequisites for an ongoing pregnancy. Studies have proven that every stage in the human reproductive process is regulated by multiple genes any problem, at step, may lead to failure (FF) or early embryonic arrest (EEA). Doctors can diagnose pathogenic factors involved FF EEA using genetic methods. With progress development of new technologies, such as single-cell RNA analysis whole-exome sequencing, a approach has opened up us directly study germ cells development. These findings will help identify unique mechanism(s) leads order find potential treatments. OBJECTIVE AND RATIONALE The goal this review compile current knowledge related EEA, clarifying mechanisms providing clues clinical diagnosis treatment. SEARCH METHODS PubMed was used search relevant research articles reviews, primarily focusing on English-language publications from January 1978 June 2023. terms included failure, arrest, genetic, epigenetic, DNA methylation, chromosome, non-coding RNA, other keywords. Additional studies were identified searching reference lists. This focuses conducted humans. However, it also incorporates data animal models when applicable. results presented descriptively, individual quality not assessed. OUTCOMES A total 233 final review, 3925 records initially. provides overview process. mutations systematically reviewed, example, globozoospermia, oocyte activation maternal effect gene mutations, zygotic genome abnormalities, chromosome epigenetic abnormalities. Additionally, summarizes treatments different defects, offering insights WIDER IMPLICATIONS information provided facilitate more accurate molecular screening tools diagnosing infertility markers networks guide practice identifying appropriate interventions based specific mutations. For obvious FF, ICSI recommended instead IVF. case defects phospholipase C zeta1 (PLCZ1), actin-like7A (ACTL7A), actin-like 9 (ACTL9), IQ motif-containing N (IQCN), fail fertilize. We consider artificial technology with improve rate reduce monetary time costs. In future, fertility expected be improved restored interfering supplementing genes.

Language: Английский

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The genetics of female and male infertility

Deutsches Ärzteblatt international, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

An estimated 17% of all couples worldwide are involuntarily childless (infertile). The clinically identifiable causes infertility can be found in the male or female partner both. molecular pathophysiology still remains unclear many cases but is increasingly being revealed by genetic analyses. This review article based on pertinent publications retrieved a selective literature search. clinical diagnostic evaluation an infertile couple may yield indication for analysis. Women with premature ovarian failure should undergo chromosomal analysis and study FMR1 gene. If congenital adrenal hypoplasia suspected, CYP21A2 gene investigated. In men, diagnosis primarily findings semen Klinefelter syndrome deletions Y-chromosomal azoospermia factors severely limit sperm production. both partners, panel selected basis individual identify cause infertility, e.g., hypogonadotropic hypogonadism, insufficiency, severe disturbances spermatogenesis. some cases, help determine likelihood success retrieval via testicular biopsy potential oocyte cryopreservation women. Genetic causes, disease patterns, related investigations becoming important have implications further treatment, children affected couple, other family members.

Language: Английский

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Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

Clinical Epigenetics, Journal Year: 2020, Volume and Issue: 12(1)

Published: Sept. 14, 2020

Abstract Background PADI6 is a component of the subcortical maternal complex, group proteins that abundantly expressed in oocyte cytoplasm, but required for correct development early embryo. Maternal-effect variants complex are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders multi-locus disturbance. While involvement infertility well demonstrated, its role less established. Results We have identified by whole-exome sequencing analysis four cases Beckwith-Wiedemann syndrome disturbance whose mothers carriers variants. In silico indicates these result loss function, segregation suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation revealed extensively altered profiles imprinted loci patients, two affected sisters, not their healthy siblings. Conclusion Our results firmly establish disorders. report loss-of-function disturbances progeny. The rare finding siblings some cases, familial recurrence risk may be high. However, phenotypes other pedigrees suggest function stochastic maintenance unpredictable consequences on embryo health.

Language: Английский

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Maternal effect genes: Update and review of evidence for a link with birth defects

Human Genetics and Genomics Advances, Journal Year: 2021, Volume and Issue: 3(1), P. 100067 - 100067

Published: Oct. 19, 2021

Maternal effect genes (MEGs) encode factors (e.g., RNA) that are present in the oocyte and required for early embryonic development. Hence, while these gene products of maternal origin, their phenotypic consequences result from effects on embryo. The first mammalian MEGs were identified mouse 2000 associated with loss offspring homozygous null females. In humans, MEG was 2006, women who had experienced a range adverse reproductive outcomes, including hydatidiform moles, spontaneous abortions, stillbirths. Over 80 have subsequently been identified, several phenotypes humans. general, pathogenic variants or absence spectrum which humans zygotic cleavage failure to multi-locus imprinting disorders. Although less established, there is also evidence structural birth defects craniofacial malformations, congenital heart defects). This review provides an updated summary reported literature through 2021, as well overview link between defects.

Language: Английский

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Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences

Clinical Epigenetics, Journal Year: 2022, Volume and Issue: 14(1)

Published: March 16, 2022

Imprinting disorders are a group of congenital diseases which characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects asymmetry. In general, single specific DMR is affected in an individual given disorder, there growing number reports on individuals so-called multilocus disturbances (MLID), where aberrant marks (most commonly loss methylation) occur multiple DMRs. However, as the literature fragmented, we reviewed data 55 previously reported or newly identified MLID families putative pathogenic variants maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) other candidate (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445).In families, total 68 different were (7 NLRP2, 16 7 17 PADI6, 15 ZFP57, variant each KHDC3L ZNF445). Clinical diagnoses offspring included Beckwith-Wiedemann syndrome spectrum, Silver-Russell transient neonatal diabetes mellitus, they suspected for disorder (undiagnosed). Some had recurrent pregnancy loss.Genomic foetal causing allow insights into mechanisms behind cycle life, spatial temporal function factors involved oocyte maturation early development. Further basic research together identification new will enable better understanding link between reproductive issues such miscarriages preeclampsia carriers/families aneuploidy observed offsprings. The current knowledge can already be employed genetic counselling situations.

Language: Английский

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DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting

Genes, Journal Year: 2021, Volume and Issue: 12(8), P. 1214 - 1214

Published: Aug. 6, 2021

Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset genes. Many these ‘imprinted’ genes mice and humans are involved embryonic extraembryonic growth development, some have life-long impacts on metabolism. During mammalian genome undergoes waves (re)programming DNA methylation other marks. Disturbances events can cause disorders compromise development. Multi-locus disturbance (MLID) condition by which defects touch more than one locus. Although most cases with MLID present clinical features characteristic disorder. Imprinting also occur ‘molar’ pregnancies-which characterized highly compromised development-and forms reproductive presenting clinically as infertility or early pregnancy loss. Pathogenic variants encoding proteins subcortical maternal complex (SCMC), multi-protein oocyte, responsible for rare subgroup moles, biparental complete hydatidiform mole (BiCHM), adverse outcomes been associated altered status embryo and/or placenta. The finding cytoplasmic protein could severe genomic at critical times gamete development has wider implications beyond relatively disorders. It signifies potential physiology, nutrition, assisted reproduction to imprinted Here, we review key milestones patterning female germline focusing humans. We provide overview recent findings regarding deficits causing BiCHM, MLID, arrest. summarize identified SCMC mutations regard arrest, MLID.

Language: Английский

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