Oocyte-specific deletion of Mitofusin1 causes female infertility and accelerated follicular depletion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA517191 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8489981_1.fastq.gz | Fastqsanger.gz | |||
| SRR8489981_2.fastq.gz | Fastqsanger.gz | |||
| SRR8489982_1.fastq.gz | Fastqsanger.gz | |||
| SRR8489982_2.fastq.gz | Fastqsanger.gz | |||
| SRR8489983_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed RNAseq analysis to determine the effect of MFN1 deletion on oocyte global gene expression profile. RNAseq revealed a total of 982 genes were significantly differentially expressed (p<0.05) in Mfn1-/- oocytes compared to WT (654 up-regulated and 337 down-regulated). Pathway analysis indicated significant over-representation of elements involved in regulation of ceramide biosynthesis, death receptor signaling and adherens junction signaling. Differential expression of these genes (Bad, G2e3, Cdh17 and Myh2) was also confirmed by qRT-PCR.Our findings provide new insight into the role of MFN1 in the oocytes, and may help understand the potential mechanism of infertility and reproductive aging associated with MFN1-deficiency.
2019-01-26 | GSE125699 | GEO
Project description:Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and competence. Follicular somatic cells play crucial roles in the growth and development of the oocyte by providing nutrients and regulatory factors. Here we investigated how oocyte quality is affected by its somatic cell environment by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed. Somatic cells within the chimeric follicle re-establish connections with the oocyte and support oocyte growth and maturation in a three-dimensional (3D) culture system. We show that young oocytes transplanted into aged follicles exhibited reduced meiotic maturation and developmental potential, whereas the young follicular environment significantly improved the rates of maturation, blastocyst formation and live birth of aged oocytes. Aged oocytes cultured within young follicles exhibited enhanced interaction with somatic cells, more youth-like transcriptome, remodelled metabolome, improved mitochondrial function, and enhanced fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat age-associated female infertility.
2024-07-22 | GSE270016 | GEO
Project description:PurposeSpontaneous oocyte activation (SOA) is a recently classified phenomenon characterized by the presence of a single pronucleus immediately following oocyte retrieval, without the apparent involvement of sperm. SOA currently remains poorly understood in humans, with no clear genetic or pathological factor(s). Herein, we report two separate cases of recurrent spontaneous oocyte activation, investigating potential avenues to identify causative etiology.MethodsTwo patients with several cycles with SOA have undergone further genetic and embryologic investigation to reveal underlying causes for SOA and provide a treatment if possible.ResultsOne case was a patient with recurrent pregnancy loss and the other was diagnosed as unexplained infertility. In the first case, 61 out of 69 oocytes retrieved exhibited SOA in five cycles while in the second case 44 out of 49 oocytes exhibited SOA in five cycles. Oocytes were injected with sperm; embryo development and presence of paternal contribution were investigated. No pregnancy is ensued following embryo transfer in both patients. Time-lapse imaging of embryogenesis from the second case did not reveal even momentary second pronucleus appearance. We also performed clinical whole exome sequencing for both patients but did not identify any disease-causing variant.ConclusionPatients with SOA suffer from infertility. Our results indicate that more investigation is required to understand the etiology of SOA in humans concentrating on the molecular mechanisms that underpin regulation of oocyte activation and calcium dynamics need to be investigated to fully understand, and perhaps in the future rectify, recurrent SOA.
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Project description:The escalating issue of infertility has become a global concern. Female infertility is primarily attributed to the decrease in both the quantity and quality of oocytes with advancing age, which is a significant factor in female infertility. The present study aims to explore the proteomic profile of exosomes obtained from human follicular fluid to identify the protein signature associated with aging and unsuccessful in vitro fertilization (IVF) outcomes. Despite the lack of significant differences in the morphology and particle size of follicular fluid exosomes between the two groups, the proteomic analysis demonstrated a distinct pattern of differentially expressed proteins. B cell activation, pathogen invasion, and disrupted metabolic processes were found to be significantly higher in the aging group, indicating the involvement of these pathways in aging-associated infertility. Moreover, the PI3K-AKT signaling pathway, which is linked to follicle maturation, was identified as the most influential signaling pathway in the aging group. In vivo experiments corroborated the weakened role of exosomes derived from the aging group in follicle maturation. Finally, the study employed a random forest machine learning algorithm, which further suggested that hydrolase activity might play a crucial role in determining the final IVF outcome. The expression of key differentially expressed proteins was validated. This study provides novel insights into the aging-associated protein signature of follicular fluid exosomes and their potential role in infertility. The findings imply that the aging-related protein signature in exosomes could serve to improve the diagnosis and treatment of infertility.
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Project description:The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.
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Project description:Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, serious daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We have previously identified Basonuclin1 (BNC1) mutation from a large Chinese POI pedigree and find the targeted Bnc1 mutation mouse exhibites POI. In this study, we find that BNC1 plays a key role in the dynamic balance of ovarian reserve, and maintaining lipid metabolism and redox homeostasis in oocytes during follicular development. Deficiency of BNC1 results in premature follicular activation and accelerated follicular atresia, but doesn’t affect the ovarian primordial follicle reserve. Mechanistically, BNC1 targets the NF2-YAP pathway to trigger oocyte ferroptosis. Inhibition of ferroptosis significantly rescues POI. These findings uncover a novel pathologic mechanism of POI based on BNC1 deficiency and is the first report showing ferroptosis involved in oocyte death.
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Project description:Oocyte maturation is vital to attain full competence required fertilization and embryogenesis. As a maternal effect factor, NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis is largely unknown. Whether NLRP14 deficiency accounts for human infertility with oocyte and embryo defects remains to be elucidated. Here, NLRP14 is identified essential for establishment of competent oocytes that can sustain early embryo development. Maternal deficiency of Nlrp14 results in sterility characterized by oocyte maturation defects and early embryo arrest. Nlrp14 ablation leads to compromised oocyte quality and developmental competence due to impaired oocyte cytoplasmic and nuclear maturation. Mechanistically, NLRP14 interacts with UHRF1 in oocyte cytoplasm to protect it from proteasome-dependent degradation, and perturbs maternal mRNA zygotic-decay and zygotic genome activation during maternal-zygotic transition. Furthermore, compound heterozygous pathogenic variants in NLRP14 gene are identified in infertile women with early embryonic arrest, which interrupt the NLRP14-UHRF1 interaction or UHRF1 protein expression. Our data uncover a vital role of NLRP14 as a new cytoplasmic-specific modulator of UHRF1 in oocyte meiotic maturation and early embryogenesis, which should provide new insights into risk prediction and genetic diagnosis for female infertility.
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Project description:Loss of ESRP1 blocks mouse oocyte development and leads to female infertility
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Project description:Total fertilization failure (TFF) is an important cause of infertility; however, the genetic basis of TFF caused by male factors remain to be clarified. In this study, whole-exome sequencing was firstly used to screen for genetic causes of TFF after intracytoplasmic sperm injection (ICSI), and homozygous variants in the novel gene IQ motif containing N (IQCN) were identified in two affected individuals with abnormal acrosome structure. Then, Iqcn knockout mice were generated by CRISPR-Cas9 technology and showed that the knockout male mice resembled TFF phenotype with oocyte activation failure. Additionally, we found that IQCN regulates the microtubule nucleation during manchette assembly via calmodulin and related calmodulin-binding proteins, which resulted in head deformity with aberrant oocyte activation factor PLCζ. Fortunately, ICSI with assisted oocyte activation can overcome IQCN-associate male infertility. Thus, our study firstly identifies the function of IQCN, highlights the relationship between the manchette assembly and fertilization, and provides a genetic marker and a therapeutic option for male-source TFF.
2022-11-22 | PXD036197 | Pride