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Molecular genetic basis of sex-specific differentiation of germ cells

生殖细胞性别特异性分化的分子遗传学基础

基本信息

批准号：
10618149
负责人：
Florence Louise Marlow
金额：
$ 49.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618149
关键词：
Adolescent Affect Affinity Chromatography Animals Binding Cell Differentiation process Cells Data Defect Development Developmental Process Female Fertility Fertilization Fishes Genes Genetic Genetic Epistasis Genetic Transcription Germ Cells Germ cell tumor Goals Growth Homologous Gene Human Infertility Maintenance Malignant Neoplasms Malignant neoplasm of ovary Maps Mediating Meiosis Mitotic Molecular Molecular Genetics Mothers Oocytes Oogenesis Organism Ovary Pathway interactions Polycystic Ovary Syndrome Premature Ovarian Failure Production Protein Isoforms Proteins RNA RNA Binding RNA Decay RNA Splicing RNA-Binding Proteins Regulation Repression Resolution Ribosomes Role Sex Bias Sex Differentiation Specific qualifier value Spermatocytes Spermatogenesis Stem Cell Research System Testing Time Transgenic Organisms Translational Repression Work Zebrafish egg gain of function gene conservation germline stem cells histone acetyltransferase insight loss of function male mutant novel ovarian reserve overexpression posttranscriptional preservation primary ovarian insufficiency programs promoter protein complex reproductive success sex sex determination sexual dimorphism sexual identity single-cell RNA sequencing spatiotemporal sperm cell stem cells translatome

项目摘要

SUMMARY The oocyte, when fertilized has the capacity to generate every cell in an organism. Efforts to understand and harness the reprogramming potential of this “mother of all stem cells” gave rise to today's stem cell research field. Despite their unique developmental potential, oocytes are highly specialized and differentiated cells. A key step in oocyte development is the transition from a mitotic germline stem cell that in most animals is specified prior to sexual differentiation to a meiotic germ cell that develops as an oocyte in females or sperm in males. Development of the oocyte is a prolonged developmental time-period characterized by highly conserved periods of meiotic activity, arrest, and substantial oocyte growth and maturation to yield a fertilizable egg. Before the first meiotic division the oocyte stops producing new RNAs. Consequently, control of programs vital to egg production and fertility rely heavily on regulation by proteins, called RNA binding proteins, that bind to RNAs and regulate their activity. Reproductive success relies on proper establishment and maintenance of sexual identity. Defects in germ cell differentiation can lead to infertility or germ cell tumors. Identifying RNA binding protein targets, and determining how they act in oocyte development is essential to fill the large gaps in our understanding of the mechanisms and molecular pathways that preserve female sex identity of the germ cells and fertility. Our long- term goal is to determine the mechanisms that regulate sex-specific programing of germ cells. We utilize the zebrafish, a powerful vertebrate genetic system to examine the mechanisms and identify genes that are crucial for successful fertility, maintenance of germ cell identity and ovarian reserve, and thus may define new molecular pathways that, when defective, can result in reduced fertility, premature ovarian insufficiency, polycystic ovary syndrome, or cancers in humans. In this proposal, mechanisms regulating sex-specific differentiation of germ cells and fertility will be tested using a combination of genetic loss of function and over expression approaches.

总结卵母细胞在受精时具有产生生物体中的每一个细胞的能力。在学懂弄通并利用这种“所有干细胞之母”的重编程潜力，研究领域。尽管卵母细胞具有独特的发育潜力，但它们是高度特化和分化的细胞卵母细胞发育的一个关键步骤是从有丝分裂的生殖系干细胞过渡，动物在性分化为减数分裂的生殖细胞之前被指定为卵母细胞，女性或男性的精子。卵母细胞的发育是一个延长的发育时期以高度保守的减数分裂活动期、停滞期和大量卵母细胞生长为特征，成熟以产生可受精的卵。在第一次减数分裂之前，卵母细胞停止产生新的RNA。因此，对卵子生产和生育至关重要的程序的控制在很大程度上依赖于蛋白质的调节，称为RNA结合蛋白，它们与RNA结合并调节其活性。生殖成功依赖于正确建立和维持性身份。缺陷生殖细胞分化可导致不育或生殖细胞肿瘤。识别RNA结合蛋白靶点，并确定它们在卵母细胞发育中的作用对于填补我们在卵母细胞发育中的巨大空白至关重要。了解保持细菌女性性别特征的机制和分子途径细胞和生育能力。我们的长期目标是确定调节性别特异性编程的机制生殖细胞我们利用斑马鱼，一个强大的脊椎动物遗传系统来研究机制，确定对成功生育、维持生殖细胞特性和卵巢储备至关重要的基因，因此可能定义新的分子途径，当有缺陷时，可能导致生育力降低，早产，卵巢功能不全、多囊卵巢综合征或人类癌症。在这项建议中，调节生殖细胞的性别特异性分化和生育力将使用遗传学的组合进行测试。功能丧失和过度表达途径。