Temporal Control of Development in C. elegans

描述（由申请人提供）：发育时间的控制对所有多细胞生物都至关重要，并且以惊人的精度实现。这项工作的目的是了解定时机制，管理特定的细胞命运的决定，在后生动物的发展，使用线虫C。elegans作为模式生物。C.线虫是全球性的时间调节器，控制着胚后发育过程中各种事件的顺序和时间。这些基因的突变改变了发育程序的相对时间，导致某些事件过早或过晚发生。本研究将主要探讨三个关键的时间调控基因lin-58、lin-42和hbl-1的分子作用。重点将是理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，并反过来将该信息传递到下游靶点的正确时间表达，lin-58突变定义了mir-48 microRNA的时间调节作用，其在发育早期起作用，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作用，表明它们具有更全面的定时功能。将确定这些基因的分子作用机制，包括保守同源结构域的分析，并通过遗传分析将它们相对于途径中的其他基因定位。一个关键的目标是确定直接与这些基因的产物相互作用的分子，并确定它们的功能。将采用各种分子和生物化学技术来实现这一目标。基因筛选将确定额外的时间调控基因。与人类健康的相关性：了解这些基因的作用机制为生物体内的细胞如何在发育和分化的特定时间停止分裂提供了一个模型。有关这种控制的知识应该有助于理解当生长控制出错时发生的问题，例如在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.