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Review
, 23 (21), 2461-77

Endoreplication: Polyploidy With Purpose

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Review

Endoreplication: Polyploidy With Purpose

Hyun O Lee et al. Genes Dev.

Abstract

A great many cell types are necessary for the myriad capabilities of complex, multicellular organisms. One interesting aspect of this diversity of cell type is that many cells in diploid organisms are polyploid. This is called endopolyploidy and arises from cell cycles that are often characterized as "variant," but in fact are widespread throughout nature. Endopolyploidy is essential for normal development and physiology in many different organisms. Here we review how both plants and animals use variations of the cell cycle, termed collectively as endoreplication, resulting in polyploid cells that support specific aspects of development. In addition, we discuss briefly how endoreplication occurs in response to certain physiological stresses, and how it may contribute to the development of cancer. Finally, we describe the molecular mechanisms that support the onset and progression of endoreplication.

Figures

Figure 1.
Figure 1.
Endoreplication. (A) Endocycles are defined as cell cycles consisting of S and G phase without cell division. Endocycling cells do not enter mitosis, and thus do not exhibit features of mitosis such as condensed chromosomes and nuclear envelope breakdown. Trichomes arise from polyploid cells that can be found on the surface of a variety of plant tissues. (The trichrome image was kindly provided by Dr. Sharon Regan, Department of Biology, Queen's University, Kingston, Ontario, Canada.) (B) Rereplication results from aberrant regulation in which DNA synthesis is initiated multiple times at individual origins of replication within a single S phase. This results in an indistinct DNA content as depicted by black lines in this hypothetical FACS profile (Y-axis is cell number and X-axis is DNA content). Green represents the diploid mitotic cell cycle profile, with 2C and 4C peaks. Red represents endoreplication cycles that result in distinct populations of cells with more than a 4C DNA content. (C) During endomitosis, cells enter mitosis and begin to condense chromosomes, but do not segregate chromosomes to daughters. Instead, they enter a G1-like state and re-enter S phase. Megakaryocytes use endomitosis upon maturation, leading to a globulated nuclear structure. Blood clot-promoting thrombocytes (or platelets) bud off of the polyploid megakaryocytes. (Cell cycle cartoons are adapted by permission from Macmillan Publishers Ltd: Nature, Zhong et al. 2003 [© 2003].)
Figure 2.
Figure 2.
Examples of endocycling tissues. (A) A schematic and image of a section of a plant embryo. The seed coat (a) covers the endosperm (b), which surrounds and provides nutrients for the growing cotyledons (c) and hypocotyl (d) of the embryo. Suspensor cells (e) arise from asymmetric division of the fertilized egg and connect the embryo to the endosperm and are thought to be crucial in nutrient transfer. (Adapted from the Ohio State University at Lima Department of Biology, courtesy of Dr. Charles Good.) (B) Drosophila ovaries consist of 12–15 ovarioles (one is shown) containing a series of developing egg chambers. The germarium (far left) houses germline and somatic stem cells that differentiate into nurse cells plus oocyte and into follicle cells, respectively. Follicle cells switch to endocycles mid-oogenesis in response to Notch signaling, which down-regulates stimulators of mitosis such as stringcdc25 and activates inhibitors of mitosis like APCfzr/cdh1. (C) Rodent TGCs are highly polyploid and facilitate embryo implantation by contributing to invasion into the uterine wall. (Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics, Rossant and Cross 2001 [© 2001].) (D) The plant hypocotyl undergoes endocycles to rapidly grow above the ground. Once the young plant reaches the sun, hypocotyl endoreplication stops. (Adapted from Dictionary.com [The American Heritage Dictionary of the English Language, © 2000 by Houghton Mifflin Company.])
Figure 3.
Figure 3.
Examples of the endoreplication during normal and cancer development.
Figure 4.
Figure 4.
Regulation of the Drosophila endocycle. A complex array of controls ensures once and only once replication during endocycle progression. The key players are shown when they are active (green, solid lines) or inactive (red, dashed lines) in either the G or S phase of the endocycle. Control of CycE/Cdk2 activity forms the core of endocycle regulation. CycE and CycE/Cdk2 activity are low during G phase when APC/Cfzr/cdh1 represses accumulation of Geminin, thereby allowing pre-RC formation. E2F stimulation of CycE transcription contributes to activation of CycE/Cdk2 and the initiation of DNA replication, which triggers E2F1 destruction. CycE/Cdk2 directly represses pre-RC formation and inactivates APC/Cfzr/cdh1, which allows Geminin accumulation that also inhibits pre-RC formation.

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