Evolution of Developmental Regulatory Pathways

描述（由申请人提供）：基因组测序的出现恢复了进化研究在生物医学研究中的中心地位，因为它们对于解释模式生物中有关调控途径的信息如何适用于人类至关重要。该领域的一个大问题是这些调控途径如何演变。三个因素使线虫成为研究进化过程的极好模型。首先，C.线虫是研究生殖生物学、细胞死亡、微小RNA、衰老和其他医生感兴趣的主题的主要焦点。其次，可用于研究这些动物的基因组和功能工具非常出色。第三，优秀的性状可供研究。例如，在线虫C. elegans和C.布里格塞这项提议描述了使用遗传和分子技术来了解C.布里格塞由于雌雄同体线虫调节性别决定途径，使XX动物产生精子，这种特征是了解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动物发育为雌雄同体的glf-1和作用于glf-1下游的glf-2。这些基因对C. briggsae，并且对于了解雌雄同体的发育起源至关重要。该项目有三个具体目标。首先是筛选与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，它的结合伴侣是理解它如何控制发育的关键。第二个目标是克隆和鉴定一个新的性别决定基因glf-2，该基因在glf-1下游起促进精子发生的作用。第三个目标涉及使用增强子和抑制子筛选来鉴定在该途径中起作用的其他基因，并表征这些基因。这些基因将是未来克隆和分子分析的候选基因。许多基因共同调节人类如何发育和对抗疾病。NIH资助的大部分基础研究都集中在这些基因如何在简单生物中发挥作用。该项目将阐明基因的功能在进化过程中如何变化，这可以帮助科学家选择研究哪些生物，并避免对其医学意义的错误推断。

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.