TEMPORAL CONTROL OF DEVELOPMENT IN C ELEGANS

这项工作的目的是了解 在发育过程中管理特定的细胞命运决定。遗传 并将使用分子方法来剖析其机制 限制外侧皮下“缝”的终末分化 线虫线虫从细胞到最后的蜕皮。当时， Seam细胞退出增殖的幼虫Seam细胞程序 执行成人终端分化程序，该过程称为 幼虫到成虫的转换(L/A转换)。转录因子 LIN-29是已知的L/A开关最直接的调节器，以及 它的活性由异时基因LIN-4、LIN-14和LIN-14决定。 28. LIN-4、LINE-14、LIN-28和LIN-29不是全套基因 调控因子的作用是使缝隙细胞终末分化。遗传 筛查将被用来识别其他基因，这些基因为L/A 换个位置。这些屏幕已经确定林-42是一架 其他重要的时间调节器。遗传和分子 对LIN-42和其他新发现的异时基因进行分析， 将被执行以确定它们在时序通路中的角色。 当蠕虫重新启动发育时 发育受阻的达尔幼虫阶段暂停 连续计时程序和L/A开关必须 已重新安排在后达尔蠕虫。基因筛查将是 以测试是否存在计时Lin-29活性的基因 尤其是在后达尔发展时期。 上游基因控制的分子机制 LIN-29活动的时间将确定。关键序列 对于LIN-29，法规将由转型救援和 LIN-29基因产物的积累模式将是 下定决心。正常的外阴也需要LIN-29的活动 在L4蜕皮期间形成。这一要求是否反映了 LIN-29在外阴/躯体性腺细胞和/或在 周围的皮下组织将通过镶嵌分析进行测试。 LIN-29功能的丧失导致成体阶段的细胞无限期 重申幼虫细胞分裂的程序，而不是刺激 细胞周期和分化。因此，林-29可以被认为是 作为抑癌基因的一般术语：其功能是 细胞周期退出所需。因此，LIN-29的时间控制 为有机体内的细胞如何指示提供了一个模型 在特定的发展时期停止分裂， 差异化。关于这种控制的知识应该有助于我们的 理解在取消增长控制时出现的问题 错误的，例如不适当地恢复细胞分裂， 发生在某些癌症中。

The aim of this work is to understand the timing mechanisms that govern specific cell fate decisions during development. Genetic and molecular methods will be used to dissect the mechanism that restricts the terminal differentiation of lateral hypodermal "seam" cells to the final molt in nematode C. elegans. At that time, the seam cells exit the proliferative larval seam cell program and execute the adult terminal differentiation program, a process called the larval-to-adult switch (L/A switch). The transcription factor LIN-29 is the most direct known regulator of the L/A switch, and its activity is timed by the heterochronic genes lin-4, lin-14, and lin- 28. The genes lin-4, line-14, lin-28 and lin-29 are not the complete set of regulators that time seam cell terminal differentiation. Genetic screens will be used to identify additional genes that time the L/A switch. These screens have already identified lin-42 as an additional important temporal regulator. Genetic and molecular analysis of lin-42, and other newly identified heterochronic genes, will be performed to determine their roles in the timing pathway. When worms reinitiate development following the developmentally-arrested "dauer larva" stage the suspends the continuous timing program and the L/A switch must be rescheduled in the post-dauer worm. Genetic screens will be performed to test if there are genes that time lin-29 activity specifically during post-dauer development. The molecular mechanism by which the upstream genes control the timing of lin-29 activity will be determined. Sequences critical for lin-29 regulation will be defined by transformation rescue and the patterns of accumulation of lin-29 gene products will be determined. Lin-29 activity is also required for proper vulva formation during the L4 molt. Whether this requirement reflects a role for lin-29 in vulva/somatic gonad cells and/or in the surrounding hypodermis will be tested by mosaic analysis. Loss of lin-29 function causes cells of the adult stage to indefinitely reiterate the larval program of cell divisions instead of exciting the cell cycle and differentiating. Thus, lin-29 can be thought of in general terms as an anti-oncogene: a gene whose function is required for cell cycle exit. Temporal control of lin-29 thus 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 our understanding of the problems that occur when growth controls go awry, such as the inappropriate resumption of cell divisions that occurs in some cancers.