Sexual development of the Drosophila gonad

果蝇性腺的性发育

• 批准号: 8018074
• 负责人: Mark B Van Doren
• 金额: $ 32.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018074
• 关键词: Adhesions; Behavior; Cadherins; Cell Adhesion Molecules; Cell-Cell Adhesion; Child; Chromatin; Data; Defect; Development; Disease; Drosophila genus; E-Cadherin; Ensure; Epigenetic Process; Exhibits; Family; Female; Fertility; Gene Expression; Genes; Germ Cells; Gonadal structure; Health; Human; Infertility; Lead; Left; Mammals; Morphogenesis; N-Cadherin; Ovary; Primordium; Production; Proteins; Recruitment Activity; Regulator Genes; Reproduction; Role; Sexual Development; Stem Cell Development; Stem cells; Syndrome; Testing; Testis; Time; Work; adult stem cell; base; cell behavior; fly; male; member; mutant; neuronal cell body; novel; sex; sex determination; sexual dimorphism; stem cell niche; stem cell population

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.

描述（由申请人提供）：生殖腺中两性异形的产生对于生殖细胞的正常发育和有性生殖至关重要。在果蝇中，睾丸和卵巢都有生殖干细胞群，这些生殖干细胞群受到各自干细胞小生境的调节，并且对于配子的连续产生至关重要。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异性相互作用，并且生殖系干细胞及其小生境在男性和女性中表现出重要的差异。在其他物种中也是如此，例如哺乳动物，其中雄性和雌性在形成生殖干细胞的能力方面表现出明显的差异。该提案的重点是了解小生境和种系干细胞在发育过程中如何形成，以及生殖细胞和索马中的性别认同如何共同控制小生境和种系干细胞中的性二态性。我们将首先研究钙粘蛋白在小生境和生殖系干细胞形成中的作用。DE-钙粘蛋白和DN-钙粘蛋白在男性和女性的发育中的生殖系干细胞龛中表达，并且定位于龛和生殖系干细胞之间的界面。我们将研究这些细胞-细胞粘附分子是否对小生境的形态发生和调节生殖干细胞的行为很重要。其次，我们将研究如何形成男性与女性的生态位是由关键的性别决定因子doublemex（dsx）调节。我们的初步数据表明，dsx调节性二型的生态位，男性生态位可能能够转分化，形成女性生态位。我们将研究dsx如何影响性腺发育过程中的生态位形成。第三，我们将研究生殖细胞中的性别决定如何与性别特异性索马相互作用以控制生殖细胞发育和生殖系干细胞形成。在果蝇和哺乳动物中，生殖细胞的性别必须与索马的性别相匹配，以保证生殖细胞的正常发育和生育能力。我们将研究为什么生殖细胞不能对不同性别的索马作出适当的反应。最后，我们将研究一个新的基因nclb在男性生殖系干细胞发育中的作用。当雄性生殖细胞成为生殖系干细胞时，NCLB在雄性生殖细胞中表达，并且NCLB突变体表现出雄性生殖系干细胞的严重损失。我们的数据表明，NCLB蛋白是一个染色质相关的因素，我们将测试的假设，NCLB是需要适当的表观遗传控制男性生殖干细胞的发展。这项工作将进一步加深我们对索马和生殖细胞的性别特异性发育如何相互作用以控制生殖系干细胞形成的理解。这项工作对我们理解人类性发育和生育能力，以及成人干细胞如何发育和受其小生境调节的更广泛问题具有明确的意义。公共卫生相关性：在这个计划中，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联合收割机来调节生殖系干细胞的形成和生育能力。这与表现出不育和/或性发育不正常的许多人类综合征有关。此外，了解干细胞小生境如何形成和调节其干细胞群体对于了解成体干细胞如何正常发挥功能以及它们的失调如何导致疾病是相关的。