Studies on Down's syndrome in tissue culture. I. Growth rates protein contents of fibroblast cultures

Segal, David J.; McCoy, Ernest E.

doi:10.1002/jcp.1040830112

Cited by 119 publications

(61 citation statements)

References 17 publications

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“…Despite the prevalence of imbalanced karyotypes in cancer, in vitro studies of aneuploid cells have not provided decisive evidence that aneuploidy alone can promote tumorigenesis. Trisomic human (Segal and McCoy 1974;Stingele et al 2012) and mouse (Williams et al 2008) cells exhibit decreased proliferation, and cells harboring mutations that promote chromosomal instability (CIN) proliferate either normally (Babu et al 2003;Jeganathan et al 2007;Weaver et al 2007) or more slowly, indicating that aneuploidy is, at best, fitness-neutral. Furthermore, studies in mouse models of CIN and Down syndrome (DS) have demonstrated that these conditions can both promote and inhibit tumorigenesis in vivo (Pfau and Amon 2012).…”

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Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

et al. 2016

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Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

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Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

et al. 2016

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“…The possibility exists that the culture condition, necessarily different from a natural environment, may enhance the process of early senescence that is characteristic of DS, [15][16][17] thereby preventing detection of proliferation deficits due to cell cycle alterations. In the current study, we were interested in establishing whether impairment of cell proliferation due to mitogenic signaling defects is a generalized feature of the trisomic condition and whether Ptch1 over expression is a common denominator for cell proliferation impairment in DS.…”

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Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

Fuchs

Ciani

Guidi

et al. 2012

Laboratory Investigation

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Down syndrome (DS) is a genetic pathology due to the triplication of human chromosome 21. In addition to mental retardation, individuals with DS exhibit a large range of variable traits, including co-occurring congenital malformations. It is now clear that neurogenesis impairment underlies the typically reduced brain size and, hence, mental retardation in individuals with DS. The small body size and the constellation of congenital malformations in children with DS suggest that proliferation defects may involve peripheral tissues, in addition to the brain. The goal of the current study was to establish whether a generalized impairment of cell proliferation is a key feature of the trisomic condition. We used the Ts65Dn mouse, a widely used DS model, and examined proliferation in tissues with different embryological origin by 5-bromo-2-deoxyuridine immunohistochemistry. We found that 2-day-old (P2) Ts65Dn mice had notably fewer proliferating cells in the heart and liver, and in all proliferating niches of the skin and intestine. A reduced proliferation rate was still present in the intestine at P15. In all tissues, Ts65Dn mice had a similar number of apoptotic cells as euploid mice, indicating no unbalance in cell death. In the skin, liver and intestine of trisomic mice, we found a higher expression of patched1 (Ptch1), a receptor that represses the mitogenic sonic hedgehog (Shh) pathway. This suggests that Ptch1-dependent inhibition of Shh signaling may underlie proliferation impairment in trisomic peripheral tissues. In agreement with the widespread reduction in proliferation, neonate trisomic mice had a reduced body weight and this defect was still present at 30 days of age. Our findings show that, in all examined peripheral tissues, Ts65Dn mice exhibit a notable reduction in proliferation rate, suggesting that proliferation impairment may be a generalized defect of trisomic precursor cells.

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“…The first studies linking aneuploidy to the decreased fitness of eukaryotic cells were conducted in primary fibroblasts from Down syndrome patients that were shown to proliferate more slowly than euploid control cells in vitro [42]. Moreover, aneuploid embryos are often characterized by slow intrauterinal growth and a lower birth weight.…”

Section: Growth Defect Of Aneuploid Cellsmentioning

confidence: 99%

The Causes and Consequences of Aneuploidy in Eukaryotic Cells

Storchová¹

2012

Aneuploidy in Health and Disease

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Studies on Down's syndrome in tissue culture. I. Growth rates protein contents of fibroblast cultures

Cited by 119 publications

References 17 publications

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

The Causes and Consequences of Aneuploidy in Eukaryotic Cells

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