Project description:Alternative splicing(AS) contributes to gene diversification through RNA-binding proteins, but AS regulation during germline development remains largely undefined. Here, we report a comprehensive set of mRNA splicing events mediated by epithelial splicing regulatory proteins 1(Esrp1) to regulate mouse oocyte development. Collectively, our data highlights that ESRP1-mediated AS program are required for oocyte development and female fertility maintainance.
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.
Project description:Maternal gene plays crucial role in the regulation of oocyte maturation and preimplantation embryonic development and its mutation is an important cause of woman infertility
Project description:Granulosa cells are essential to the growth, development, and maturation of oocytes and follicles. In patients with EMs-related infertility, follicle maturation disorders, poor oocyte quality may be closely related to GCs in the follicle. However, the molecular biological mechanism of GCs in EMs-related infertility has not been reported. Therefore, we tried to explore the possible causes of EMs-related infertility through the study of ovarian GCs in patients with EMs-related infertility and tubal factor infertility.
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.
Project description:Premature ovarian insufficiency (POI) refers to the loss of ovarian function before the age of 40, which is among the various contributing factors towards infertility issues. Several studies have previously reported dominantly inherited POI symptoms in families carrying likely contributing heterozygous EIF4ENIF1 mutations. However, this impact of EIF4ENIF1 haploinsufficiency was barely studied in animal models to reveal the underlying molecular changes that relate to infertility. In this study, we demonstrated that haploinsufficiency of Eif4enif1 caused mouse subfertility, impaired oocyte maturation and partial early embryo developmental arrest. By dual-omic sequencing, we revealed that Eif4enif1-deficiency led to significantly altered transcriptome and translatome in mouse oocytes, which led to the further discovery of abnormal mitochondrial hyperfusion with altered mitochondria-associated ribonucleoprotein domain (MARDO) distribution in Eif4enif1-dificient oocytes. This study provided new insight into the molecular mechanism underlying clinical fertility failures, and added new evidences to discovering new therapeutic targets towards infertility.
Project description:ESRP1 is an epithelial-specific splicing factor. It mainly regulates expressions of genes related to intercellular adhesion, actin cytoskeleton, cell polarity and cell migration at the post-transcriptional level by alternative splicing. It also plays an important role in the development and progression of cancers. This study analyzed the transcriptome changes of ESRP1 stably overexpression SKOV3 cells by high-throughput sequencing, discovered and validated the functional effects of ESRP1 on ovarian cancer cells
Project description:Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that spermidine level was reduced in aged ovaries and supplementation of spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By micro-transcriptomic analysis, we further discovered that recovery of oocyte quality by spermidine was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this action mechanism was conserved in porcine oocytes under oxidative stress. Altogether, our findings demonstrate that spermidine supplementation is a potentially effective strategy to ameliorate oocyte quality and reproductive outcome of women at an advanced age.