Temporal Control of Development in C. elegans

描述(由申请人提供)：对发育时间的控制对所有多细胞生物体都是至关重要的，并以惊人的精度实现。这项工作的目的是了解在后生动物发育过程中控制特定细胞命运决定的时间机制，以线虫线虫为模式生物。线虫的异时基因是一种全球性的时间调节因子，在胚胎后发育过程中控制着不同事件的顺序和时间。这些基因的突变改变了发育程序的相对时间，导致某些事件发生得太早或太晚。本研究将主要研究三个关键的时间调控基因：LIN-58、LIN-42和HBL-1的分子作用。重点将集中在了解这些基因如何从层次结构中上游作用的基因接收时间信息，并进而将这些信息传递到下游靶标的正确时间表达，LIN-58突变定义了mir-48 microRNA的时间调节作用，而LIN-42和HBL-1的不同之处在于，它们的分析揭示了早期和晚期的作用，表明它们具有更全局的计时功能。这些基因的作用分子机制(S)将被确定，包括保守的同源结构域的分析，并将通过遗传分析相对于途径中的其他基因进行定位。一个关键的目标是识别与这些基因的产物直接相互作用的分子，并确定它们的功能。为了实现这一目标，将采用各种分子和生化技术。基因筛查将识别额外的时间调控基因。与人类健康相关：了解这些基因的作用机制，为有机体内的细胞如何被指示在发育和分化的特定时间停止分裂提供了一个模型。对这种控制的了解应该有助于理解当生长控制出错时会出现的问题，例如某些癌症中发生的细胞分裂的不适当恢复。

DESCRIPTION (provided by applicant): Control of developmental time is of fundamental importance to all multicellular organisms and is achieved with astonishing precision. The aim of this work is to understand the timing mechanisms that govern specific cell fate decisions during metazoan development, using the nematode C. elegans as a model organism. The heterochronic genes of C. elegans are global temporal regulators that control the sequence and timing of diverse events during postembryonic development. Mutations in these genes alter the relative timing of developmental programs, causing certain events to occur too early or too late. This research will primarily investigate the molecular roles of three key temporal regulatory genes: lin-58, lin-42, and hbl-1. Emphasis will be directed at understanding how these genes receive temporal information from genes acting upstream in the hierarchy and in turn relay that information to correctly time expression of downstream targets, lin-58 mutations define temporal regulatory role for the mir-48 microRNA, which acts early in development, while lin-42 and hbl-1 are distinct in that their analysis reveals both early and late roles suggesting they have a more global timing function. Molecular mechanism(s) of action of these genes will be determined, including analysis of conserved homology domains, and they will be positioned with respect to others in the pathway through genetic analysis. A key goal is to identify molecules that interact directly with the products of these genes and to determine their function. A variety of molecular and biochemical techniques will be employed to achieve this aim. Genetic screens will identify additional temporal regulatory genes. Relevance to human health: Understanding the mechanisms by which these genes act provides a model for how cells within an organism are instructed to cease dividing at a specific time in development and differentiate. Knowledge about this control should aid in the understanding of the problems that occur when growth controls go awry, such as the inappropriate resumption of cell divisions that occurs in some cancers.