Evolution of Developmental Regulatory Pathways

描述(申请人提供)：基因组测序的出现使进化研究恢复到生物医学研究的中心位置，因为它们对于解释关于模式生物中调控途径的信息如何应用于人类是必不可少的。该领域的一大问题是，这些监管途径是如何演变的。有三个因素使线虫成为研究进化过程的极佳模型。首先，线虫是生殖生物学、细胞死亡、微RNA、衰老和其他医生感兴趣的课题的主要研究重点。其次，可用于处理这些动物的基因组和功能工具非常出色。第三，优良性状可供研究。例如，在线虫秀丽线虫和线虫C.briggsae中，两性发育是独立进化的。这项建议描述了利用遗传和分子技术来了解布里奇萨斯的两性发育是如何进化的实验。由于两性线虫调节性别决定途径，从而允许XX动物产生精子，这一特征是研究进化过程中调节途径如何变化的理想选择。到目前为止，我们已经鉴定并克隆了导致XX动物两性发育的GLF-1和GLF-2，GLF-2作用于GLF-1的下游。这些基因是新发现的，对于了解两性生殖发育的起源是至关重要的。这个项目有三个具体目标。第一个是筛选与GLF-1相互作用的蛋白质。由于GLF-1是一类新的F-box蛋白的成员，它的结合伙伴是理解它如何控制发育的关键。第二个目标是克隆和鉴定GLF-2，这是一种新的性别决定基因，作用于GLF-1下游，促进精子发生。第三个目标涉及使用增强子和抑制子筛选来识别在这一途径中起作用的其他基因，并对这些基因进行表征。这些基因将成为未来克隆和分子分析的候选基因。许多基因相互协作，调节人类的发育和抗击疾病的方式。由美国国立卫生研究院资助的大部分基础研究通过在简单生物中研究这些基因是如何发挥作用的。这个项目将阐明基因的功能在进化过程中是如何变化的，这可以帮助科学家选择研究哪些生物，并避免对它们的医学意义做出错误的推断。

DESCRIPTION (provided by applicant): The advent of genome sequencing restored evolutionary studies to a central place in biomedical research, since they are essential for interpreting how information about regulatory pathways in model organisms might apply to humans. One of the big questions in the field is how these regulatory pathways evolve. Three factors make nematodes an excellent model for studying evolutionary processes. First, C. elegans is a major focus of study about reproductive biology, cell death, micro-RNAs, aging, and other subjects of interest to physicians. Second, the genomic and functional tools available for working with these animals are outstanding. Third, excellent traits are available for study. For example, hermaphrodite development evolved independently in the nematodes C. elegans and C. briggsae. This proposal describes experiments that use genetic and molecular techniques to learn how hermaphroditic development evolved in C. briggsae. Since hermaphrodite nematodes modulate the sex-determination pathway to allow XX animals to make sperm, this trait is ideal for learning how regulatory pathways change during evolution. So far, we have identified and cloned glf-1, which causes XX animals to develop as hermaphrodites, and glf-2, which acts downstream of glf-1. These genes are novel to C. briggsae, and critical to learning how hermaphrodite development originated. This project has three specific aims. The first is to screen for proteins that interact with GLF-1. Since GLF-1 is a member of a new class F-box proteins, its binding partners are the key to understanding how it controls development. The second aim is to clone and characterize glf-2, a new sex-determination gene that acts downstream of glf-1 to promote spermatogenesis. The third aim involves the use of enhancer and suppressor screens to identify additional genes that act in this pathway, and to characterize these genes. These genes would be candidates for future cloning and molecular analyses. Many genes cooperate to regulate how humans develop and fight disease. Much of the basic research funded by the NIH focuses on how these genes work by studying them in simple creatures. This project will elucidate how the functions of genes change during evolution, which could help scientists choose which creatures to study, and avoid mistaken inferences about their medical significance.