Genetic control of animal development

描述（由申请人提供）：C。elegans模型系统是研究体内控制细胞分裂和分化的遗传和分子机制的理想系统。我们专注于表皮的“缝细胞”，经历了刻板的模式划分整个幼虫的发展，然后在成年期的终端分化。缝细胞表现出干细胞样行为，包括通过不对称或对称细胞分裂的自我更新。缝细胞的对称和不对称细胞分裂的执行是由我们实验室已经广泛表征的发育时序机制调节的。在该项目的第一个目标中，我们将探索发育时序调节器如何与影响细胞分裂极性的途径相互作用，以控制接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，以确定新的基因，影响调控的对称与不对称细胞分裂缝细胞。第三个目标将利用C。elegans作为研究干细胞静止机制的模型。哺乳动物成体干细胞通常在增殖和静止状态之间转换，这取决于细胞外信号。在静止期，干细胞的活力和发育潜力被维持很长一段时间。我们建议了解机制，控制干细胞维持在静止期的dauer幼虫发育停滞。Dauer幼虫是一种可选的发育停滞的第二阶段幼虫，其是响应于不利于生长的环境条件而诱导的。在Dauer幼虫中，接缝细胞进入静止状态，值得注意的是，这种静止深刻地影响了接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。研究发育静止期与发育时序调节因子的相互作用。elegans细胞谱系应该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。 公共卫生相关性：C. elegans是一个很好的系统，用于动物发育过程的遗传分析，包括细胞分裂、细胞数量和细胞分化的控制。由于许多控制C. elegans的发育也在哺乳动物中发现，了解它们在C. elegans应该揭示包括人类在内的所有动物共同的发育过程的机制和原则。

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.