Cell competition in the developing mouse germline

发育中的小鼠种系中的细胞竞争

• 批准号: 8731294
• 负责人: Diana J Laird
• 金额: $ 5.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731294
• 关键词: Adhesions; Amoeba genus; Assisted Reproductive Technology; Biogenesis; Biological; Cell Lineage; Cells; Chordata; Development; Drosophila genus; Embryo; Embryonic Development; Epiblast; Epigenetic Process; Evolution; Exhibits; Gene Expression; Gene Mutation; Genetic; Genetic Screening; Germ Cells; Goals; Gonadal Ridge; Gonadal structure; Growth; Individual; Mammals; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Organism; Phenotype; Pluripotent Stem Cells; Regulator Genes; Risk; Stem cells; Structure of primordial sex cell; Transplantation; Work; abstracting; base; cancer diagnosis; fitness; in vivo; in vivo Model; insight; migration; mutant; public health relevance; sex; social; trait; tumor; tumor progression

DESCRIPTION (Provided by the applicant) Abstract: Competition between cells within organisms has been recognized in social amoebae, Drosophila, and the inception and metastasis of cancer. "Winner" cells exhibit advantages in growth, adhesion or survival, putatively increasing the overall fitness of the individual organism. However, only competition among germ cells results in direct inheritance of "winner" traits. As gametes are established during early embryonic development from primordial germ cells (PGCs), heritable genetic mutations that undergo selection and drive evolution of species must occur in this cell lineage. I previously demonstrated germline stem cell competition in a basal chordate and recent work hints at a parallel phenomenon in mammals. Our goal is to determine the gene regulatory and genetic bases for germ cell competition in mice. We will study competition among PGCs in the mouse embryo in three aspects of their development: the allocation of pluripotent epiblast cells to the germline, the migration of PGCs to the gonadal ridges, and the expansion of PGCs in the embryonic gonad as they commence sex-specific differentiation. To model in vivo competition among isogenic PGCs, we will employ genetic marking strategies; comparison of "winning" PGC clones to unpurified or non-dominant ones will reveal gene expression and epigenetic differences that potentially bestow an advantage to developing germ cells. To model competitive advantage by genetic alteration, we will employ 7 different PGC mutants that we previously identified in a forward genetic screen of mouse embryos. We will use transplantation approaches to pit these PGC depletion, overabundance and migration phenotypes against one another in vivo and ask how a particular genetic mutation impacts fitness to enter the germline, migrate, and contribute to gamete biogenesis. We hope to gain a molecular understanding of how PGCs interact with their niches and provide insight into basic regulatory and genetic mechanisms of cellular selection that underlie evolution and tumorogenesis. Public Health Relevance: Since the origin and progression of cancer occurs by cells gaining a selective advantage in survival, proliferation or migration, study of the mechanism of cell competition will identify genetic alterations, regulatory or epigenetic changes that become dysregulated in tumor development and could be useful in cancer diagnosis or targeted for therapy. In assisted reproductive technologies, where the prospect of differentiating gametes from pluripotent stem cells looms on the horizon, understanding germ cell competition will be instrumental to informing the potential risks and biological consequences of short circuiting in vivo germ cell development.

描述（由申请人提供） 摘要：生物体内细胞之间的竞争已在社会变形虫、果蝇以及癌症的发生和转移中得到认识。 “获胜者”细胞在生长、粘附或存活方面表现出优势，推测可以提高个体生物体的整体适应性。然而，只有生殖细胞之间的竞争才会导致“获胜者”性状的直接遗传。由于配子是在早期胚胎发育过程中由原始生殖细胞 (PGC) 形成的，因此经历选择并驱动物种进化的可遗传基因突变必须发生在该细胞谱系中。我之前证明了基底脊索动物中的生殖系干细胞竞争，最近的工作暗示了哺乳动物中的类似现象。我们的目标是确定小鼠生殖细胞竞争的基因调控和遗传基础。我们将研究小鼠胚胎中 PGC 之间在发育过程中三个方面的竞争：多能外胚层细胞向种系的分配、PGC 向性腺嵴的迁移以及胚胎性腺中 PGC 在开始性行为时的扩张。具体区别。为了模拟同基因 PGC 之间的体内竞争，我们将采用遗传标记策略；将“获胜”PGC克隆与未纯化或非显性克隆进行比较将揭示基因表达和表观遗传差异，这些差异可能为发育中的生殖细胞带来优势。为了通过遗传改变来模拟竞争优势，我们将采用我们之前在小鼠胚胎的正向遗传筛选中鉴定出的 7 种不同的 PGC 突变体。我们将使用移植方法在体内将这些 PGC 耗尽、过剩和迁移表型相互比较，并探究特定的基因突变如何影响进入种系、迁移和促进配子生物发生的适应性。我们希望从分子水平上了解 PGC 如何与其生态位相互作用，并深入了解进化和肿瘤发生的细胞选择的基本调控和遗传机制。 公共健康相关性：由于癌症的起源和进展是由细胞在生存、增殖或迁移中获得选择性优势而发生的，因此对细胞竞争机制的研究将识别在肿瘤发展过程中失调的遗传改变、调控或表观遗传变化，这些变化可能会导致癌症的发生。可用于癌症诊断或靶向治疗。在辅助生殖技术中，将配子与多能干细胞分化的前景迫在眉睫，了解生殖细胞竞争将有助于了解体内生殖细胞发育短路的潜在风险和生物学后果。

项目成果

Humans put their eggs in more than one basket.

人类把鸡蛋放在不止一个篮子里。

• 发表时间: 2013-01
• 影响因子: 21.3
• 作者: Laird; Diana J
• 通讯作者: Diana J

Patterning of sharp cellular interfaces with a reconfigurable elastic substrate.

使用可重构弹性基底对尖锐的细胞界面进行图案化。

• 发表时间: 2017-01-23
• 作者: Curtis, Allison;Li, David J;DeVeale, Brian;Onishi, Kento;Kim, Monica Y;Blelloch, Robert;Laird, Diana J;Hui, Elliot E
• 通讯作者: Hui, Elliot E