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

点击翻译按钮获取中文摘要

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.