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

在大多数动物物种中，基因组中的内在遗传程序和营养可用性等外部因素决定了细胞生长（质量积累）和增殖（细胞数量增加）的速率。协调这两个过程对于在发育过程中确定最终组织尺寸至关重要。虽然过去二十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，但对控制这些过程的调控网络却知之甚少。 E2 F家族转录因子是重要的增殖调节因子，其功能在所有多细胞生物中是保守的。它们确保了细胞周期正常进行所必需的基因的及时表达。我的NSERC研究的重点是调查dE 2F 1活性在发育过程中的调节机制，使用果蝇作为模型系统。由于果蝇只有一个E2 F，dE 2F 1，它提供了发育所需的所有促增殖功能，因此它是研究E2 F生物学的一个简单而优秀的系统。TSC/Tor途径控制细胞大小和组织生长以响应外部因素。我的实验室以前发现dE 2F 1表达受TSC/Tor通路调节，确定了将生长调节与细胞周期联系起来的遗传网络。最近，我们产生了突变果蝇，其中dE 2F 1的表达不再受TSC/Tor途径的调节。对突变果蝇的分析揭示了两个令人惊讶的发育缺陷。首先，不能响应于生长促进信号增加dE 2F 1表达的细胞经历细胞死亡。这证明了将细胞生长与增殖偶联的功能重要性，并表明消除异常细胞的故障安全机制。第二，突变雌性的生育力严重降低，表明TSC/Tor-dE 2f 1调控网络在卵子发生过程中特别重要。在本NSERC提案中，我们将重点关注以下具体目标。 1.研究TSC/Tor途径调节dE 2F 1表达的分子机制。 2.研究消除生长和增殖不协调的细胞的故障安全机制的功能意义。 3.研究TSC/Tor-dE 2F调控网络在卵子发生过程中的生物学作用。 总的来说，拟议的研究将提高我们目前对协调细胞生长和增殖的调控网络的理解，并为发育过程中的器官大小调控提供新的见解。

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.