Sexual development of the Drosophila gonad

描述(由申请人提供)：在性腺中创造性别二态对于生殖细胞的正常发育和有性繁殖是至关重要的。在果蝇中，睾丸和卵巢都有生殖系干细胞群体，它们受各自的干细胞生态位调控，对于持续产生配子是必不可少的。生殖系干细胞的形成需要生殖细胞和体细胞性腺之间的特定相互作用，生殖系干细胞及其生态位在雄性和雌性之间都表现出重要的差异。在哺乳动物等其他物种中也是如此，在这些物种中，雄性和雌性在形成生殖系干细胞的能力方面表现出明显的差异。这项建议侧重于了解在发育过程中壁龛和生殖系干细胞是如何形成的，以及生殖细胞和体体中的性别认同如何共同作用来控制壁龛和生殖系干细胞中的性别二型性。我们将首先研究钙粘附素在巢干细胞和生殖系干细胞形成中的作用。De-钙粘蛋白和dN-钙粘蛋白在雄性和雌性生殖系干细胞的发育过程中均有表达，并定位于生殖系干细胞和生殖系干细胞之间的界面。我们将研究这些细胞-细胞黏附分子是否对壁龛的形态发生和生殖系干细胞的行为调控很重要。其次，我们将研究关键的性别决定因子双性(Dsx)是如何调节雄性与雌性生态位的形成。我们的初步数据表明，DSX调节了生态位中的性别二型性，并且雄性生态位可能能够反式分化形成雌性生态位。我们将研究在性腺发育过程中，双链淀粉如何影响生态位的形成。第三，我们将研究生殖细胞中的性别决定如何与性别特异的胞体相互作用，以控制生殖细胞的发育和生殖系干细胞的形成。在果蝇和哺乳动物中，生殖细胞的性别必须与体细胞的性别匹配，才能正常发育生殖细胞和生育能力。我们将调查为什么生殖细胞不能对异性的胞体做出适当的反应。最后，我们将研究一种新基因NCLB在男性生殖系干细胞发育中的作用。NCLB在雄性生殖细胞成为生殖系干细胞时表达，而NCLB突变体表现出雄性生殖系干细胞的严重丧失。我们的数据表明，NCLB蛋白是一种染色质相关因子，我们将检验NCLB是男性生殖系干细胞发育的适当表观遗传控制所必需的假设。这项拟议的工作将进一步加深我们对体细胞和生殖细胞的性别特异性发育如何相互作用来控制生殖系干细胞形成的理解。这项工作对我们理解人类的性发育和生育能力，以及成体干细胞如何发育和受其生态位调控这一更广泛的问题有着明显的影响。公共卫生相关性：在这项提案中，我们将研究生殖细胞和体细胞性腺的适当性发育如何结合起来调节生殖系干细胞的形成和生育能力。这与许多表现出不孕不育和/或性发育不正常的人类综合征有关。此外，了解干细胞如何形成和调节干细胞群体，对于理解成体干细胞的正常功能以及它们的错误调控如何导致疾病是相关的。

DESCRIPTION (provided by applicant): The creation of sexual dimorphism in the gonad is critical for proper germ cell development and sexual reproduction. In Drosophila, both the testis and ovary have germline stem cell populations that are regulated by their respective stem cell niches and are essential for continuous production of gametes. Germline stem cell formation requires specific interactions between the germ cells and somatic gonad, and both the germline stem cells and their niches exhibit important differences in males and females. This is also true in other species, such as mammals, where the male and female exhibit clear differences in their ability to form germline stem cells. This proposal focuses on understanding how the niches and germline stem cells are formed during development, and how sexual identity in the germ cells and soma work together to control sexual dimorphism in the niche and germline stem cells. We will first study the role of the cadherins in the formation of the niche and germline stem cells. DE-cadherin and DN-cadherin are expressed in the develoinvestigatorng germline stem cell niche in both males and females, and are localized to the interface between the niche and germline stem cells. We will investigate whether these cell-cell adhesion molecules are important for morphogenesis of the niche and for regulating the behavior of the germline stem cells. Second, we will study how the formation of the male vs. female niche is regulated by the critical sex determination factor doublesex (dsx). Our preliminary data indicate that dsx regulates sexual dimorphism in the niche and that the male niche may be able to trans- differentiate to form the female niche. We will study how dsx influences niche formation during gonad development. Third, we will study how sex determination in the germ cells interacts with a sex-specific soma to control germ cell development and germline stem cell formation. In flies, as well as mammals, the sex of the germ cells must match the sex of the soma for proper germ cell development and fertility. We will investigate why germ cells fail to respond appropriately to a soma of a different sex. Finally, we will investigate the role of a new gene, no child left behind (nclb), in male germline stem cell development. nclb is expressed in male germ cells at the time they become germline stem cells, and nclb mutants exhibit a severe loss of male germline stem cells. Our data indicate that the NCLB protein is a chromatin-associated factor and we will test the hypothesis that NCLB is required for proper epigenetic control of male germline stem cell development. The proposed work will further our understanding of how sex-specific development of the soma and germ cells interact to control germline stem cell formation. This work has clear implications for our understanding of human sexual development and fertility, as well as the broader question of how adult stem cells develop and are regulated by their niches. PUBLIC HEALTH RELEVANCE: In this proposal, we will study how proper sexual development of the germ cells and somatic gonad combine to regulate germline stem cell formation and fertility. This is relevant to the many human syndromes that exhibit infertility and/or improper sexual development. Further, an understanding of how stem cell niches form and regulate their stem cell population is relevant for understanding how adult stem cells normally function and how their misregulation can result in disease.