NuA4 and Ecdysone Impact Cell Cycle Gene Expression to Regulate the Proper Timing of Cell Cycle Exit in Drosophila.

[摘要] During organogenesis, many cells undergo a process called terminal differentiation, where cells acquire their final fates and begin to perform essential physiological functions. Terminal differentiation is often accompanied by a transition to a non-dividing state, called cell cycle exit. As development proceeds, many cells exit the cell cycle, and most cells in mature organisms remain in a non-dividing, post-mitotic state. Despite its prevalence, how the transition from a proliferative to a post-mitotic state is induced and maintained is not fully understood. In this thesis, I examine two aspects of cell cycle gene regulation that are essential for the proper transition of Drosophila epithelial cells from a proliferative to a post-mitotic state during development. In part 1 I describe a novel, critical role for the NuA4 chromatin remodeling and histone exchange complex in promoting the proper timing of cell cycle exit in vivo.Unlike other chromatin binding factors that repress cell cycle genes, NuA4 does not directly inhibit cell proliferation. NuA4 instead suppresses a previously unknown intrinsic DNA damage response that occurs during late S-phase. My work revealed that suppression of this endogenous DNA damage response is required in vivo to properly coordinate S and G2 cell cycle progression with differentiation and cell cycle gene expression during tissue development. In part 2, I examine how steroid hormone signaling plays a central role in coordinating the timing of cell cycle exit. Pulses of the steroid hormone ecdysone trigger a cascade of gene expression changes required to coordinate cell maturation with differentiation and cell cycle exit in insects. Here I reveal that ecdysone signaling in the Drosophila wing induces a transcription factor Broad that represses the expression of an essential mitosis promoting gene, the cdc25c phosphatase, to cause a G2-phase cell cycle arrest. After the ecdysone pulse, as Broad expression declines, the cdc25c phosphatase becomes re-expressed, which in turn promotes rapid mitotic entry into a synchronized final cell cycle and cell cycle exit. Altogether, my work has revealed two essential signaling pathways that impact cell cycle gene expression and cell cycle progression to properly coordinate cell cycle exit with terminal differentiation during development.

[发布机构] University of Michigan

[效力级别] proliferation

[关键词] cell cycle exit;proliferation;DNA damage;cell cycle checkpoint;ecdysone;development;Genetics;Molecular;Cellular and Developmental Biology;Science (General);Science;Molecular, Cellular, and Developmental Biology