Genetic regulation of ovariole development in Drosophila

描述(申请人提供)：所有动物的繁殖成功取决于性腺的发育和功能，性腺负责产生和传递卵子和精子。在人类中，卵巢的完整性和排卵量是健康、生育和繁殖力的关键决定因素。因此，了解动物如何调节卵巢发育对于推进生物医学研究至关重要。将成为卵巢的细胞首先在人类和果蝇的胚胎发育过程中被搁置。然后，它们在人类的胎儿发育和苍蝇的幼虫发育过程中增殖。生殖细胞将继续产生卵子和精子，在此期间也会增殖，与卵巢的体细胞密切接触。生殖细胞和体细胞的增殖被认为是协调的，但这种协调的细节却鲜为人知。任何一种细胞类型的不正确增殖都可能导致肿瘤和卵巢癌，这往往会导致人类不育。因此，很明显，不同卵巢细胞类型的生长协调是生育和生殖健康的关键决定因素，但我们不知道这种生长是如何调节的，从而实现每种细胞类型的适当数量。该项目的具体目标是(1)了解细胞在卵巢早期发育过程中经历的发育过程；(2)了解被称为河马通路的信号通路在这一过程中的作用，该通路与许多人类癌症密切相关；(3)了解河马通路如何与其他基因相互作用来指导卵巢发育。为了达到第一个目的，我们比较了不同卵巢数的果蝇的卵巢发育。这告诉我们，未来的工作应该关注两个关键的发育阶段：第一，胚胎发育的最早阶段，细胞第一次被搁置；第二，这些细胞增殖，产生产生卵巢小管所需的正确数量的细胞的后期。为了我们的第二个目标，我们将研究河马途径如何在正常卵巢发育过程中发挥作用。河马途径基因的突变与几种类型的人类癌症有关，包括人类的卵巢癌和生殖系统癌。最后，为了我们的第三个目标，我们研究了河马途径与之相互作用的其他潜在信号和生长基因，以指导卵巢发育。这显然与人类健康有关，因为几种生殖障碍和癌症与河马信号缺陷有关。因此，更多地了解河马信号在正常卵巢发育中的作用是我们研究的重要优先事项。

DESCRIPTION (provided by applicant): Reproductive success of all animals depends on the development and function of the gonads, which are responsible for producing and delivering eggs and sperm. Among humans, ovarian integrity and output are key determinants of health, fertility and fecundity. Understanding how animals regulate ovarian development is therefore critical to advance biomedical research. The cells that will become the ovary are first set aside in embryonic development in both humans and fruit flies. They then proliferate throughout fetal development in humans, and larval development in flies. Germ cells, which will go on to produce eggs and sperm, also proliferate during this time, in close contact with the somatic cells of the ovary. It is thought that germ cell and somatic cell proliferation are coordinated, but the detailsof this coordination are poorly understood. Incorrect proliferation of either cell type can lead to tumors and ovarian cancer, which often cause sterility in humans. It is therefore clear that the coordination of growth in different ovarian cell types is a critical determinant of fertility and reproductive health, but we do not know how this growth is regulated so that the proper number of each cell type is achieved. The specific Aims of this project are (1) to understand the developmental processes that cells undergo during early ovarian development; (2) to understand the role in this process of a signaling pathway called the Hippo pathway, which is strongly implicated in many human cancers; (3) to understand how the Hippo pathway interacts with other genes to direct ovarian development. For the first Aim, we have compared ovarian development in fly species with very different ovariole numbers. This has taught us that there are two critical stages of development that future work should be focused on: first, the earliest stages of embryogenesis when cells are first set aside; and second, the later period when these cells proliferate to create the correct number of cells needed to make ovarioles. For our second Aim, we will investigate how the Hippo pathway functions during normal ovarian development. Mutations in Hippo pathway genes are linked to several types of human cancers, including cancers of the ovary and reproductive system in humans. Finally, for our third Aim, we examine the other potential signaling and growth genes that the Hippo pathway interacts with to direct ovarian development. This has clear relevance to human health, since several reproductive disorders and cancers are associated with defective Hippo signaling. Understanding more about the role of Hippo signaling in normal ovarian development is thus an important priority in our research.