Genetic control of animal development

描述（申请人提供）：秀丽隐杆线虫模型系统是研究体内细胞分裂和分化控制的遗传和分子机制的理想选择。我们将重点放在表皮“缝细胞”上，这些细胞在幼虫发育过程中经历了一种刻板的分裂模式，随后在成年期发生了终末分化。接缝细胞表现出类似干细胞的行为，包括通过不对称或对称细胞分裂进行自我更新。缝细胞的对称和非对称细胞分裂是由发育定时机制调控的，我们的实验室已经对这一机制进行了广泛的研究。在该项目的第一个目标中，我们将探索发育定时调节因子如何与影响细胞分裂极性的途径相连接，以控制缝细胞何时从不对称细胞分裂切换到对称细胞分裂。第二个目标将扩展这些研究，以确定影响缝细胞中对称与不对称细胞分裂调节的新基因。第三个目标将利用秀丽隐杆线虫作为模型来研究控制干细胞静止的机制。哺乳动物成体干细胞通常在增殖和静止状态之间转换，取决于细胞外信号。在静息期，干细胞的活力和发育潜力可以维持较长时间。我们建议了解在大鼠幼虫发育停滞期间控制干细胞维持的机制。大鼠幼虫是一种选择性发育受阻的第二阶段幼虫，是在不利生长的环境条件下诱导的。在dawer幼虫中，缝细胞进入休眠状态，这种休眠状态深刻影响了缝细胞对某些发育调控基因的反应，包括进化上保守的lin-4和let-7 microRNA基因。研究秀丽隐杆线虫细胞系的发育静止如何与发育时间调节因子相互作用，将揭示与人类生物学相关的干细胞行为的基本原理，包括发育、癌症、组织稳态和伤口愈合。

DESCRIPTION (provided by applicant): The C. elegans model system is ideal for studying the genetic and molecular mechanisms of the control of cell division and differentiation in vivo. We focus on the epidermal "seam cells" that undergo a stereotyped pattern of divisions throughout larval development, followed by terminal differentiation at adulthood. Seam cells exhibit stem-cell- like behavior, including self-renewal through either asymmetric or symmetric cell division. The execution of symmetric and asymmetric cell divisions by seam cells is regulated by developmental timing mechanisms that have been extensively characterized in our lab. In the first Aim of the project, we will explore how developmental timing regulators interface with pathways affecting cell division polarity to control when seam cells switch from asymmetric to symmetric cell division. The second Aim will extend these studies to identify new genes that affect the regulation of symmetric vs. asymmetic cell divisions in seam cells. The third Aim will utilize C. elegans as a model to study the mechanisms governing stem cell quiescence. Mammalian adult stem cells commonly transition between proliferative and quiescent states, depending on extracellular signals. During quiescence, a stem cell's vitality and developmental potential is maintained for extended periods of time. We propose to learn about mechanisms that controlling stem cell maintenance during quiescence in dauer larva developmental arrest. The dauer larva is an optional developmentally-arrested second stage larva that is induced in response to environmental conditions unfavorable for growth. In dauer larvae, the seam cells enter quiescence, and remarkably, this quiescence profoundly affects how seam cells respond to certain developmental regulatory genes, including the evolutionarily conserved lin-4 and let-7 microRNA genes. Studying how developmental quiescence interacts with developmental timing regulators in C. elegans cell lineages should reveal fundamental principles of stem cell behavior relevant to human biology, including development, cancer, tissue homeostasis and wound healing. PUBLIC HEALTH RELEVANCE: C. elegans is an excellent system for the genetic analysis of developmental processes in animals, including the control of cell division, cell number, and cellular differentiation. Since many of the proteins and other regulatory molecules that control C. elegans development are also found in mammals, understanding their roles in C. elegans should reveal the mechanisms and principles underlying developmental processes common to all animals, including humans.