RESUMO
Reproductive diseases are a long-standing problem and have become more common in the world. Currently, 15% of the world's population suffers from infertility, and half of them are women. Maturation of oocytes, successful fertilization, and high-quality embryos are prerequisites for pregnancy. With the development of assisted reproductive technology and advanced genetic assays, we have found that infertility in many young female patients is caused by mutations in various developmental regulators. These pathogenic factors may result in impediment of oocyte maturation, failure of fertilization or early embryonic development arrest. In this review, we categorize these clinically-identified, mutated genetic factors by their molecular characteristics: nuclear factors (PALT2, TRIP13, WEE2, TBPL2, REC114, MEI1 and CDC20), cytoplasmic factors (TLE6, PADI6, NLRP2/5, FBXO43, MOS and BTG4), a factor unique to primates (TUBB8), cell membrane factor (PANX1), and zona pellucida factors (ZP1-3). We compared discrepancies observed in phenotypes between human and mouse models to provide clues for clinical diagnosis and treatment of related reproductive diseases.
Assuntos
Proteínas F-Box , Infertilidade Feminina , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Ciclo Celular , Conexinas/genética , Conexinas/metabolismo , Desenvolvimento Embrionário/genética , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Fertilização/genética , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Masculino , Camundongos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Oócitos/metabolismo , Gravidez , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/genética , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/metabolismo , Tubulina (Proteína)RESUMO
BACKGROUND: Enhancer of zeste homologue 2 (EZH2), the core member of polycomb repressive complex 2 (PRC2), has multiple splicing modes and performs various physiological functions. However, function and mechanism of alternative splicing at Ezh2 exon 3 in reproduction are unknown. METHODS: We generated Ezh2Long and Ezh2Short mouse models with different point mutations at the Ezh2 exon 3 alternative splicing site, and each mutant mouse model expressed either the long or the short isoform of Ezh2. We examined mutant mouse fertility and oocyte development to assess the function of Ezh2 alternative splicing at exon 3 in the reproductive system. RESULTS: We found that Ezh2Long female mice had normal fertility. However, Ezh2Short female mice had significantly decreased fertility and obstructed oogenesis, with compromised mitochondrial function in Ezh2Short oocytes. Interestingly, increased EZH2 protein abundance and accumulated H3K27me3 were observed in Ezh2Short oocytes. CONCLUSIONS: Our results demonstrate that correct Ezh2 alternative splicing at exon 3 is important for mouse oogenesis.
Assuntos
Processamento Alternativo , Proteína Potenciadora do Homólogo 2 de Zeste , Oócitos , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Éxons/genética , Feminino , Camundongos , Oócitos/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismoRESUMO
The number and quality of oocytes in the ovarian reserve are related to fertility and reproductive lifespan in mammals. Some transcription factors have been demonstrated to determine oogenesis. The insulinoma-associated 2 (Insm2) gene is a member of the Snail transcriptional repressor superfamily. Recent studies have demonstrated Insm2 plays an essential role for insulin secretion and glucose intolerance in mice, but the functions of Insm2 in reproduction remain elusive. Here, by examination of Insm2 knockout mice, we found Insm2 was essential for female fertility. Loss of Insm2 resulted in female infertility with major defects in primordial follicle pool, ovarian folliculogenesis and ovulation. Transcriptomic profiling of ovaries suggests that loss of Insm2 caused defects in oocyte meiosis and steroid synthesis. Both oocyte- and granulosa cell-expressed genes were dysregulated, including Foxo1 and other known genes involved in primary ovarian insufficiency. Together, these studies show that Insm2 is required for oocyte development and their communication with ovarian somatic cells.
Assuntos
Infertilidade Feminina , Reserva Ovariana , Animais , Feminino , Camundongos , Infertilidade Feminina/genética , Mamíferos , Camundongos Knockout , Oócitos/metabolismo , Esteroides , Fatores de Transcrição/metabolismoRESUMO
N,N-dimethylformamide (DMF) is a widely-used solvent for the synthesis of synthetic fibers such as polyacrylonitrile fiber, and can also be used to make medicine. Although this organic solvent has multipurpose applications, its biological toxicity cannot be ignored and its impact on mammalian reproduction remains largely unexplored. Our study found that DMF exposure inhibited oocyte maturation and fertilization ability. Transcriptomic analysis indicated that DMF exposure changed the expression of genes and transposable elements in oocytes. Subcellular structure examination found that DMF exposure caused mitochondrial dysfunction, abnormal aggregation of mitochondria and decreased mitochondrial membrane potential in mouse oocytes. Its exposure also caused abnormal distribution of Golgi apparatus and endoplasmic reticulum which formed large number of clusters. In addition, oxidative stress occurs in oocytes exposed to DMF, which was manifested by an increase in the level of reactive oxygen species. We found that DMF exposure induced disordered spindle and chromosomes abnormality. Meanwhile, we examined various histone modification levels in oocytes exposed to DMF and found that DMF exposure reduced H3K9me3, H3K9ac, H3K27ac, and H4K16ac levels in mouse oocytes. Moreover, DMF-treated oocytes failed to form pronuclei after fusion with normal sperm. Collectively, DMF exposure caused mitochondrial damage, oxidative stress, spindle assembly and chromosome arrangement disorder, leading to oocyte maturation arrest and fertilization failure.