Molecular genetic basis of sex-specific differentiation of germ cells

摘要 受精后的卵母细胞有能力生成生物体中的每一个细胞。努力了解 利用这种“所有干细胞之母”的重新编程潜能，产生了今天的干细胞。 研究领域。尽管卵母细胞具有独特的发育潜力，但它们高度特化和分化。 细胞。卵母细胞发育的一个关键步骤是从有丝分裂生殖系干细胞过渡到大多数 动物在有性分化之前被指定为减数分裂生殖细胞，该生殖细胞在 雌性或雄性的精子。卵母细胞的发育是一个较长的发育时期。 减数分裂的特征是减数分裂活动、停滞和大量卵母细胞生长的高度保守的时期和 成熟后产生可受精卵。在第一次减数分裂之前，卵母细胞停止产生新的RNA。 因此，对产卵和受精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， 被称为RNA结合蛋白，它与RNA结合并调节其活性。 生殖的成功依赖于适当的性别认同的建立和维持。中的缺陷 生殖细胞分化可能导致不育或生殖细胞肿瘤。鉴定RNA结合蛋白 靶点，并确定它们在卵母细胞发育中的作用，对于填补我们的 了解细菌保持雌性性别认同的机制和分子途径 细胞和生育能力。我们的长期目标是确定管理特定性别节目的机制 生殖细胞。我们利用斑马鱼，一种强大的脊椎动物遗传系统来研究机制和 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，以及 因此可以定义新的分子通路，当缺陷时，可能会导致生育力降低，早产 卵巢功能不全、多囊卵巢综合征或人类癌症。在这项提案中，机制 调节生殖细胞的性别特异性分化和生育能力将使用基因组合进行测试 功能丧失和过度表达方式。

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.