Control by tra-1 of sexual differentiation in C. elegans

两性异形是几乎所有动物发育的基本特征，并影响体内许多组织和细胞类型。 在秀丽隐杆线虫中，一个基因tra-1的活性是必要的，足以决定整个身体发育为雄性还是雌性。 如果tra-1是活跃的，所有的组织分化为女性，而如果tra-1是不活跃的，所有的组织分化为男性。因此tra-1是研究性别分化的理想候选基因。 此外，C.线虫是进行这种研究的理想生物，因为两性差异很大，可以在单细胞水平上分析发育，而且存在强大的分子和遗传工具。 在这个项目中，我想回答两个基本问题：首先，由tra-1调控的基因mab-3是如何调控男性性发育和行为的;其次，tra-1在性腺和性别特异性肌肉中控制哪些基因。tra-1的活性如何指导性分化？ 为了找到答案，我建议用两种方法研究受tra-1调控的基因。 第一个是检测mAb-3，这是我们之前发现的一个tra-1靶基因，它控制着男性感觉器官的发育，也是男性行为所必需的。 mAb-3与昆虫和脊椎动物中的性调节因子有关，这表明性发育在远亲动物中通过类似的机制发生。 DMRT 1是与mAb-3相关的基因，与人类睾丸发育和性逆转综合征有关。 我们将使用遗传筛选来鉴定由mAb-3调控的对感觉器官发育重要的基因。 我们还将研究哪些感觉神经元需要mAb-3来维持男性行为。 第二种方法是鉴定受tra-1控制的新基因。 为了找到这些基因，我们将使用DNA微阵列，它使我们能够快速识别来自两性的性别特异性mRNA。 我们将使用RNA干扰（RNAi）来测试性别特异性基因的功能，并研究感兴趣的基因的表达。 从这个筛选中，我们将选择少量的基因进行进一步的研究，集中在那些似乎直接受tra-1调控，并在发育早期作用于性腺和肌肉组织的特定性别特异性分化的基因上。 这些实验将最终揭示tra-1如何控制性别分化的分子细节。

Sexual dimorphism is a fundamental feature of development in virtually all animals, and affects many tissues and cell types in the body. In the nematode Caenorhabditis elegans, the activity of a single gene, tra-1, is necessary and sufficient to dictate whether the entire body develops as male or female. If tra-1 is active, all tissues differentiate as female, whereas if tra-1 is inactive, all tissues differentiate as male. Thus tra-1 is an ideal candidate with which to study sexual differentiation. In addition, C. elegans is an ideal organism in which to perform such studies because the two sexes differ extensively, development can be analyzed at the single cell level, and powerful molecular and genetic tools exist. In this project I want to answer two basic questions: first, how does mab-3, a gene regulated by tra-1, regulate male sexual development and behavior, and second, what genes does tra-1 control in the gonad and in sex-specific muscles. How does the activity of tra-1 direct sexual differentiation? To find out, I propose to study genes that are regulated by tra-1, using two approaches. The first is to examine mab-3, a tra-1 target gene we identified previously that controls male development of sense organs and also is required for male behavior. mab-3 is related to sexual regulators in insects and vertebrates, suggesting that sexual development occurs by similar mechanisms in distantly related animals. DMRT1, a gene related to mab-3, is implicated in human testis development and sex reversal syndromes. We will use genetic screens to identify genes regulated by mab-3 that are important for sense organ development. We also will study which sensory neurons require mab-3 for male behavior. The second approach is to identify new genes that are controlled by tra-1. To find these genes we will use DNA microarrays, which allow us to rapidly identify sex- specific mRNAs from the two sexes. We will use RNA interference (RNAi) to test the functions of sex-specific genes and will study the expression of those of interest. From this screen, we will select a small number of genes for further study, concentrating on those that appear to be directly regulated by tra-1 and act early in development to specific sex-specific differentiation of the gonad and musculature. These experiments will ultimately reveal in molecular detail how tra-1 controls sexual differentiation.