Analysis of Nematode Sex Determination

描述（由申请人提供）：一个长期目标是了解线虫中指定性命运的基因开关。在这种生物和其他生物中，性别是由X染色体计数机制决定的，该机制将一条X染色体与两条X染色体区分开来。x染色体剂量本身并不足以决定性别。相反，X染色体的数量是相对于常染色体的数量进行评估的，即X:A比率。我们发现X上的一组基因，称为X信号元件（XSEs），通过转录和转录后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）的基因反对xse的抑制活性，使xol-1活性在XO胚胎中高而在XX胚胎中低。未来的工作将解决如何只有两倍范围内的浓度调节可以指定两种不同的性命运。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，它结合XX动物的两个X染色体来抑制一半的X表达。复合体的成员在有丝分裂和减数分裂染色体的压实和分解中也起着重要的作用。我们发现X上离散的顺式作用位点作为进入位点招募复合体并使复合体沿X向核扩散，未来的工作将解决X识别位点的分子身份、扩散机制和抑制的生化基础。染色体分离和基因表达之间的联系对人类疾病有进一步的影响。

DESCRIPTION (provided by applicant): One long-term goal is to understand the genetic switch that specifies sexual fate in the nematode C. elegans. Sex is determined in this and other organisms by an X-chromosome counting mechanism that distinguishes one X chromosome from two. X-chromosome dose by itself is not sufficient to determine sex. Instead, X-chromosome number is assessed relative to the sets of autosomes, the X:A ratio. 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 post-transcriptional mechanisms. Another set of genes called Autosomal-signal elements (ASEs) opposes the repressive activity of XSEs, allowing xol-1 activity to be high in XO embryos and low in XX embryos. Future work addresses how only a two-fold range in the concentration of regulators can specify two alternative sexual fates. 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 Xchromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex 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 and resolution of mitotic and meiotic chromosomes. We found that discrete, cis-acting sites on X act as entry sites to recruit the complex and to nucleate spreading of the complex along X. Future work addresses the molecular identity of the X-recognition sites, the mechanism of spreading, and the biochemical basis for repression. The link between chromosome segregation and gene expression has further implications for human disease.