ANALYSIS OF NEMATODE SEX DETERMINATION

线虫性别决定分析

• 批准号: 3278518
• 负责人: BARBARA J MEYER
• 金额: $ 23.74万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3278518
• 关键词: Caenorhabditis elegans; Drosophilidae; autoradiography; autosome; biological signal transduction; cell cell interaction; complementary DNA; cytogenetics; developmental genetics; endonuclease; fluorescence microscopy; gene complementation; gene dosage; gene expression; genetic regulation; genetic transcription; hermaphroditism; lethal genes; male; meiosis; molecular cloning; nondisjunction; nucleic acid hybridization; nucleic acid sequence; sex chromosomes; sex determination

Our long-term goals are two-fold, (1) to understand, in genetic and molecular terms, the basis for the male/hermaphrodite decision in the nematode C. elegans and (2) to understand the mechanism of X chromosome dosage compensation at the genetic and molecular levels. The primary sex-determining signal in C. elegans is the X/A ratio; 2X/2A animals are hermaphrodite, and IX/2A animals are male. How the primary sex-determining signal is assessed and subsequently translated into the choice of either the hermaphrodite or male mode of sexual development re- mains a mystery, but is a primary focus of this grant. We have acquired significant insight into understanding the basis of the male/hermaphrodite decision by demonstrating that the sex determination and dosage compensation processes share common early steps prior to their divergence into two separate pathways. The hermaphrodite mode is coordinately controlled by at least two genes, sdc-I and sdc-2; the male mode is controlled by xol-l. The sdc genes appear to play a role in either assessing the X/A ratio or transmitting this signal to both the sex determination and dosage compensation pathways. Genetic interactions suggest that xol-l is the earliest acting gene in the known hierarchy that controls the male/hermaphrodite decision and is likely to be the gene nearest to the primary sex-determining signal. A fourth gene, dpy,-29, is also involved in controlling both processes, and illustrates a paradoxical feedback between dosage compensation disruptions and sex determination. Further insight into the male/hermaphrodite decision will be sought by: (1) Identification and analysis of additional genes central to both sex determination and dosage compensation. (2) A mosaic analysis of sdc-2, xol-l and dpy-29 to determine when the sex determination decision is made and whether it is a cell autonomous process or whether it involves factors extrinsic to the cell, such as diffusible products or cell-cell interactions. (3) An extensive molecular analysis of the genes that play a central role in the male/hermaphrodite decision, sdc-1, sdc-2, xol-l and dpy-29. The molecular analysis will include discerning how these genes are regulated in response to the X/A signal, (or how they help assess the X/A ratio), as well as how they regulate each other and the downstream sex determination and dosage compensation genes. The molecular characterization of these early-acting components of the sex determination decision will be the first molecular analysis of genes that control both processes in this organism. Further insight into the mechanism of X chromosome dosage compensation will be sought by: (1) Identification and analysis of additional dosage compensation genes. (2) Molecular characterization of two genes critical to the process, dpy-27 and dpy-28. This represents the first molecular characterization of dosage compensation genes in this organism. Elucidating the mechanism of sex determination will provide fundamental insight into developmental processes that go awry in human diseases.

我们的长期目标有两个，（1）了解遗传和 分子术语，男性/雌雄同体决定的基础 线虫和秀丽隐杆线虫（2）了解X染色体的机制 遗传和分子水平上的剂量补偿。 线虫的主要性别决定信号是 X/A 比率； 2X/2A 动物是雌雄同体，IX/2A 动物是雄性。初级如何 性别决定信号被评估并随后转化为 选择雌雄同体或雄性的性发育模式 这是一个谜，但却是这笔赠款的主要焦点。我们已经获得了 对理解男性/雌雄同体的基础有重要的洞察力 通过证明性别决定和剂量来做出决定 薪酬流程在出现分歧之前有共同的早期步骤 分成两条独立的路径。雌雄同体模式是协调的 由至少两个基因sdc-I和sdc-2控制；男性模式是 由xol-l控制。 sdc 基因似乎在以下任一方面发挥作用 评估 X/A 比率或将此信号传输给两性 测定和剂量补偿途径。遗传相互作用 表明 xol-l 是已知层次结构中最早起作用的基因 控制男性/雌雄同体的决定，很可能是基因 最接近主要性别决定信号。第四个基因，dpy，-29，是 也参与控制这两个过程，并说明了一个矛盾的问题 剂量补偿中断和性别决定之间的反馈。 通过以下方式进一步了解男性/雌雄同体的决定：(1) 鉴定和分析对两性都至关重要的其他基因 测定和剂量补偿。 (2) sdc-2的镶嵌分析， xol-l 和 dpy-29 确定何时做出性别决定决定 是细胞自主过程还是涉及因素 细胞外来的，例如可扩散产物或细胞-细胞 互动。 (3) 对发挥作用的基因进行广泛的分子分析 在雄性/雌雄同体决定中发挥核心作用，sdc-1、sdc-2、xol-l 和 dpy-29。分子分析将包括辨别这些基因如何 响应 X/A 信号进行调节，（或者它们如何帮助评估 X/A 比率），以及它们如何相互调节以及下游性别 决定和剂量补偿基因。分子表征 这些性别决定决定的早期作用成分将是 首次对控制这两个过程的基因进行分子分析 生物。 进一步深入了解X染色体剂量补偿机制将 通过以下方式寻求： (1) 额外剂量的识别和分析 补偿基因。 (2) 两个关键基因的分子特征 进程 dpy-27 和 dpy-28。这代表了第一个分子 该生物体中剂量补偿基因的表征。 阐明性别决定机制将为我们提供基础 深入了解人类疾病中出错的发育过程。