Analysis of Nematode Sex Determination

描述（由申请人提供）：剂量敏感信号在发育过程中细胞命运决定中起重要作用。我们研究的一个领域是研究分子信号的微小数量差异转化为显著不同的发育命运的机制。我们的长期目标之一是剖析线虫的定量信号和基因开关，这些信号和基因开关指定了线虫的性命运。秀丽隐杆线虫通过计算相对于倍体的X染色体数目来决定性别，即常染色体组（X:A信号）。我们发现X上的一组基因，称为X信号元件（XSEs），通过转录和mrna前机制通过抑制性别决定开关基因xol-1的活性来传递X染色体剂量。另一组称为常染色体信号元件（ase）的基因通过拮抗xse激活xol-1来传递倍性。Xol-1指定了活跃时的雄性命运和不活跃时的雌雄同体命运。我们的工作研究了xse和ase相互拮抗以决定性别的分子机制。其中一个XSE是一种名为sex1的核激素受体（NHR），它是维甲酸受体（RAR）基因家族的同源物，参与所有后生动物中用于模式和细胞分化的信号通路。rar的破坏与人类癌症有关，这一知识已导致在白血病治疗中使用类维生素a。从秀丽隐杆线虫等模式生物中获得的关于nhr功能的遗传途径的信息将为发现其他可能适用于人类的药物治疗基因靶点提供机会。第二个长期目标是了解X染色体剂量补偿机制，使两性之间的X表达均衡。我们定义了一种蛋白质复合物（DCC），它可以结合XX动物的两个X染色体，从而抑制一半的X表达。该复合体的成员在有丝分裂和减数分裂染色体的压实、分解和分离以及同源减数分裂染色体之间的遗传重组控制中也起着重要作用。蛋白质复合物不仅对基因的表达和生存能力至关重要，而且大多数成分对基因组的稳定也至关重要。因此，研究剂量补偿将有助于我们理解染色体分离错误和减数分裂重组中断所引起的基因组不稳定性。我们已经确定了针对DCC抑制X染色体的顺式作用调控元件，并发现了DCC识别和结合X的基本原理。我们未来的工作将探索染色体结构、DCC结合和全染色体基因抑制之间的联系。

DESCRIPTION (provided by applicant): Dose-sensitive signals play essential roles in cell fate decisions during development. One area of our research investigates mechanisms by which small quantitative differences in molecular signals are translated into dramatically different developmental fates. One of our long-term goals is to dissect the quantitative signals and the genetic switch that specifies sexual fate in the nematode C. elegans. C. elegans determines sex by tallying X-chromosome number relative to the ploidy, the sets of autosomes (X:A signal). We showed that a set of genes on X, called X signal elements (XSEs), relays X-chromosome dose by repressing the activity of the sex determination switch gene xol-1 through both transcriptional and pre-mRNA mechanisms. Another set of genes called autosomal signal elements (ASEs) communicates ploidy by antagonizing the XSEs to activate xol-1. xol-1 specifies the male fate when active and the hermaphrodite fate when inactive. Our work investigates molecular mechanisms by which XSEs and ASEs antagonize each other to determine sex. One XSE is a nuclear hormone receptor (NHR) called SEX-1, a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. A second long-term goal is understand the mechanism of X-chromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex (DCC) that binds both X chromosomes of XX animals to repress X expression by half. Members of the complex also play essential roles in the compaction, resolution, and segregation of mitotic and meiotic chromosomes as well as the control of genetic recombination between homologous meiotic chromosomes. Not only is the protein complex essential for proper gene expression and viability, most components are essential for genome stability. Thus, studying dosage compensation will help us understand genomic instability caused by errors in chromosome segregation and disruption of meiotic recombination. We have identified cis-acting regulatory elements that target the X chromosome for repression by the DCC and discovered fundamental principles by which the DCC recognizes and binds X. Our future work will explore the connection between chromosome structure, DCC binding, and chromosome-wide gene repression.