Distinct responses to reduplicated chromosomes require distinct Mad2 responses

Stormo, Benjamin M; Fox, Donald T.

doi:10.7554/elife.15204

Cited by 27 publications

(26 citation statements)

References 78 publications

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“…This led us to hypothesize that inhibition of mitotic cyclins in the adult pylorus may prevent entry into mitotic cycles after injury. Fizzy-related (Fzr), the Drosophila homolog of mammalian FZR1/CDH1, is a binding partner of the APC/C, which facilitates degradation of mitotic cyclins including Cyclin B. Fzr is also a well-known regulator of the endocycle in many cell types ( Lehner and O'Farrell, 1989 ; Schaeffer et al, 2004 ; Sigrist and Lehner, 1997 ; Stormo and Fox, 2016 ) and fzr mutant cells can ectopically undergo mitotic cycles instead of endocycles ( Schaeffer et al, 2004 ; Schoenfelder et al, 2014 ; Sigrist and Lehner, 1997 ). Thus, increased fzr expression in the adult pylorus is a plausible mechanism for the altered injury responses we observe.…”

Section: Resultsmentioning

confidence: 99%

Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut

Cohen

Allen

Sawyer

et al. 2018

eLife

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Ploidy-increasing cell cycles drive tissue growth in many developing organs. Such cycles, including endocycles, are increasingly appreciated to drive tissue growth following injury or activated growth signaling in mature organs. In these organs, the regulation and distinct roles of different cell cycles remains unclear. Here, we uncover a programmed switch between cell cycles in the Drosophila hindgut pylorus. Using an acute injury model, we identify mitosis as the response in larval pyloric cells, whereas endocycles occur in adult pyloric cells. By developing a novel genetic method, DEMISE (Dual-Expression-Method-for-Induced-Site-specific-Eradication), we show the cell cycle regulator Fizzy-related dictates the decision between mitosis and endocycles. After injury, both cycles accurately restore tissue mass and genome content. However, in response to sustained growth signaling, only endocycles preserve epithelial architecture. Our data reveal distinct cell cycle programming in response to similar stimuli in mature vs. developmental states and reveal a tissue-protective role of endocycles.

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Section: Resultsmentioning

confidence: 99%

Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut

Cohen

Allen

Sawyer

et al. 2018

eLife

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“…Asymmetrical chromosomal separation has been confirmed in polyploid human megakaryocytes [ 44 ] and is a common phenomenon in tetraploid cells [ 45 ]. Finally, genomic reduplication was suggested to result in diplochromosomes characterized by tightly associated quartets of centromeres and chromosome arms [ 46 ]. To circumvent this, we determined DNA content of isolated trophoblasts by FACS analysis and screened for CNVs by performing whole-genome sequencing (WGS) in combination with BIC-seq analysis.…”

Section: Discussionmentioning

confidence: 99%

Genome amplification and cellular senescence are hallmarks of human placenta development

et al. 2018

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Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.

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“…Rectal papillar cell division requires elimination of polytene chromosome structure, which is a barrier to proper cell division. Polytene separation occurs in a process known as Separation Into Recent Sisters, or SIRS (Stormo and Fox 2016). To prepare for SIRS, papillar cells transiently eliminate cohesins between sister chromatids during each round of the premitotic endocycle (Stormo and Fox 2019).…”

Section: Hindgut Developmentmentioning

confidence: 99%

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

et al. 2020

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The insect excretory system contains two organ systems acting in concert: the Malpighian tubules and the hindgut perform essential roles in excretion and ionic and osmotic homeostasis. For over 350 years, these two organs have fascinated biologists as a model of organ structure and function. As part of a recent surge in interest, research on the Malpighian tubules and hindgut of Drosophila have uncovered important paradigms of organ physiology and development. Further, many human disease processes can be modeled in these organs. Here, focusing on discoveries in the past 10 years, we provide an overview of the anatomy and physiology of the Drosophila excretory system. We describe the major developmental events that build these organs during embryogenesis, remodel them during metamorphosis, and repair them following injury. Finally, we highlight the use of the Malpighian tubules and hindgut as accessible models of human disease biology. The Malpighian tubule is a particularly excellent model to study rapid fluid transport, neuroendocrine control of renal function, and modeling of numerous human renal conditions such as kidney stones, while the hindgut provides an outstanding model for processes such as the role of cell chirality in development, nonstem cell–based injury repair, cancer-promoting processes, and communication between the intestine and nervous system.

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Distinct responses to reduplicated chromosomes require distinct Mad2 responses

Cited by 27 publications

References 78 publications

Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut

Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut

Genome amplification and cellular senescence are hallmarks of human placenta development

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

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