ANALYSIS OF NEMATODE SEX DETERMINATION

我们的长期目标是双重的，（1）了解，在遗传和 分子术语，男性/雌雄同体决定的基础， 线虫C.（2）了解X染色体的机制 基因和分子水平的剂量补偿。 C. elegans是X/A比率; 2X/2A 动物为雌雄同体，IX/2A动物为雄性。第一次如何 评估性别决定信号，随后将其转化为 选择雌雄同体或男性的性发育模式， 主要是一个谜，但这是一个主要的重点补助金。我们获得 对理解男性/雌雄同体的基础有重要的见解 通过证明性别决定和剂量 薪酬流程在出现分歧之前， 分成两个独立的通道雌雄同体的模式是协调的 由至少两个基因sdc-I和sdc-2控制，雄性模式为 由xol-1控制。sdc基因似乎在以下两个过程中发挥作用： 评估X/A比率或将此信号传递给性别 确定和剂量补偿途径。遗传相互作用 表明xol-1是已知层次中最早起作用的基因， 控制雄性/雌雄同体的决定，很可能是基因 最接近主要的性别决定信号。第四个基因dpy-29， 也参与控制这两个过程，并说明了一个矛盾的 剂量补偿中断和性别决定之间的反馈。 进一步深入了解男性/雌雄同体的决定将寻求：（1） 鉴定和分析对两性都重要的其他基因 测定和剂量补偿。(2)sdc-2的镶嵌分析， xol-1和dpy-29来确定何时做出性别决定 以及它是否是一个细胞自主的过程， 细胞外的，如扩散产物或细胞-细胞 交互. (3)一项对基因的广泛分子分析显示， 在雄性/雌雄同体决定中的中心作用，sdc-1，sdc-2，xol-l和 dpy-29。分子分析将包括辨别这些基因是如何 调节响应X/A信号，（或它们如何帮助评估X/A信号） 比例），以及它们如何相互调节和下游性别 决定和剂量补偿基因。的分子特征 性别决定的这些早期作用成分中， 第一次对控制这两个过程的基因进行分子分析， 有机体 对X染色体剂量补偿机制的进一步深入了解将有助于我们更好地理解X染色体剂量补偿机制。 （1）确定和分析额外剂量 补偿基因(2)两个关键基因的分子特征 该过程，dpy-27和dpy-28。这代表了第一个 在这种生物体中的剂量补偿基因的表征。 阐明性别决定的机制将为性别决定的研究提供基础 对人类疾病中出错的发育过程的深入了解。

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.