Investigating the genetic network that coordinates the growth and cell cycle regulation.

在大多数动物物种中，基因组中固有的遗传程序和外部因素，如营养的可获得性，决定了细胞的生长(大量积累)和增殖(细胞数量的增加)的速度。协调这两个过程对于确定发育过程中最终的组织大小至关重要。尽管过去20年的研究已经确定了控制细胞大小和细胞分裂的单个基因和途径，但管理这些过程的调控网络却鲜为人知。 E2F转录因子家族是重要的增殖调节因子，其功能在所有多细胞生物体中都是保守的。它们确保了正常细胞周期进程所必需的基因的及时表达。我的NSERC研究重点是以果蝇为模型系统，研究dE2F1活性在发育过程中的调节机制。由于果蝇只有一种E2F，即dE2F1，它提供了发育所需的所有促增殖功能，因此它是研究E2F生物学的一个简单但却很好的系统。TSC/Tor途径调控细胞大小和组织生长，对外界因素做出反应。我的实验室以前发现，dE2F1的表达受TSC/Tor途径的调控，确定了一个将生长调控与细胞周期联系起来的遗传网络。最近，我们培育了dE2F1表达不再受TSC/Tor途径调控的突变果蝇。对突变果蝇的分析发现了两个令人惊讶的发育缺陷。首先，对促生长信号不能增加dE2F1表达的细胞会经历细胞死亡。这证明了将细胞生长与增殖相结合的功能重要性，并提出了一种消除异常细胞的故障保护机制。其次，突变雌体的育性严重降低，表明TSC/Tor-dE2f1调控网络在卵子发生过程中尤为重要。在NSERC的这项提案中，我们将重点关注以下具体目标。 1.探讨TSC/Tor途径调控dE2F1表达的分子机制。 2.探讨消除细胞生长和增殖不协调的故障安全机制的功能意义。 3.研究TSC/Tor-dE2F调控网络在卵子发生过程中的生物学作用。 总体而言，拟议的研究将改善我们目前对协调细胞生长和增殖的调控网络的理解，并为发育过程中器官大小的调控提供新的见解。

Intrinsic genetic programs wired in the genome and external factors such as nutrient availability determine the rate of cellular growth (mass accumulation) and proliferation (increase in cell number) in most animal species. Coordinating these two processes is essential for defining the final tissue size during development. While studies over past two decades have identified individual genes and pathways that control cell size and cell division, the regulatory networks that govern these processes are less understood. E2F family of transcription factors are vital regulators of proliferation whose functions are conserved among all multicellular organisms. They ensure timely expression of genes that are necessary for proper cell cycle progression. My NSERC research focuses on investigating the mechanism by which dE2F1 activity is regulated during development using the fruit fly as a model system. Because fruit flies have only one E2F, dE2F1, that provides all the pro-proliferative function necessary for development, it is a simple yet an excellent system to study E2F biology. The TSC/Tor pathway governs cell size and tissue growth in response to external factors. My lab has previously discovered that dE2F1 expression is regulated by the TSC/Tor pathway, identifying a genetic network that links growth regulation to the cell cycle. More recently, we generated mutant flies in which dE2F1 expression is no longer regulated by the TSC/Tor pathway. Analysis of the mutant flies revealed two surprising developmental defects. First, cells that fail to increase dE2F1 expression in response to the growth promoting signal undergo cell death. This demonstrates the functional importance of coupling cellular growth to proliferation and suggests a failsafe mechanism that eliminates abnormal cells. Second, the fertility of mutant female is severely reduced, indicating that the TSC/Tor-dE2f1 regulatory network is particularly important during oogenesis. In this NSERC proposal, we will focus on the following specific aims. 1. Investigating the molecular mechanism by which the TSC/Tor pathway regulates dE2F1 expression. 2. Investigating the functional significance of the failsafe mechanism that eliminates cells with uncoordinated growth and proliferation. 3. Investigating the biological role of the TSC/Tor-dE2F regulatory network during oogenesis. Overall, the proposed research will improve our current understanding on the regulatory network that coordinates cellular growth and proliferation and provide novel insights into organ size regulation during development.