The pattern of X-chromosome inactivation in the embryonic and extra-embryonic tissues of post-implantation digynic triploid LT/Sv strain mouse embryos

Speirs, S.; Cross, Jane; Kaufman, M. H.

doi:10.1017/s0016672300035175

Cited by 9 publications

(8 citation statements)

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“…Similar findings have previously been reported in connection with triploid embryos recovered from LT/Sv strain mice at a similar stage of gestation (Speirs & Kaufman, 1989;Speirs et al 1990). Similar findings have previously been reported in connection with triploid embryos recovered from LT/Sv strain mice at a similar stage of gestation (Speirs & Kaufman, 1989;Speirs et al 1990).…”

Section: Discussionsupporting

confidence: 90%

The differential staining pattern of the X chromosome in the embryonic and extraembryonic tissues of postimplantation homozygous tetraploid mouse embryos

1992

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C57BL x CBA)F1 hybrid female mice were mated with hemizygous Rb(X.2)2Ad males to distinguish the paternal X chromosome. Homozygous tetraploids were produced by blastomere fusion at the 2-cell stage, and 161 of these were transferred to recipients and analysed on the 10th day of gestation. 59 implants contained resorptions and 76 contained either an embryo and/or extraembryonic membranes. 38 (20, XXXX and 18, XXYY) were analysed to investigate their X-inactivation pattern. Embryonic and yolk sac endodermally-and mesodermally-derived samples were analysed by G-banding and by Kanda analysis. In the XX and XY controls, the predicted pattern of X-inactivation was observed, though 12-2% of metaphases in the XX series displayed no X-inactivation. In the XY series the Y chromosome was seen in a high proportion of metaphases.In the XXXX tetraploids, 8 cell lineages were recognized with regard to their X-inactivation pattern, though most belonged to the following 3 categories: (XmXm)XpXp, Xm(XmXp)Xp and XmXm(XpXp). The other categories were only rarely encountered. In the embryonic and mesodermally-derived tissue the ratio of these groups was close to 1:2:1, whereas in the endodermally-derived tissue it was 1:4-11:4-88, due to preferential paternal X-inactivation. A significant but small proportion of all 3 tissues analysed displayed no evidence of X-inactivation. Indirect evidence suggests that this represents a genuine group because of the high efficiency of the Kanda staining. The presence of the Xm(XmXp)Xp category is consistent with the expectation that X-inactivation occurs randomly in 2 of the 4 X chromosomes present. The presence of small numbers of preparations with no evidence of X-inactivation and other unexpected categories suggests that these are probably selected against during development.

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Section: Discussionsupporting

confidence: 90%

The differential staining pattern of the X chromosome in the embryonic and extraembryonic tissues of postimplantation homozygous tetraploid mouse embryos

1992

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“…However, in vivo the number of choice rounds may be less than ten, resulting in more cells with too many Xa's, which would be selected against. This is supported by observations made in female embryos that show a significant number of cells with two Xa's after completion of the X inactivation process [21], [49]. Our simulations also predict less cells with too many Xi's than we detected in vivo , especially for the 4n XXXX and XXXY cells.…”

Section: Discussionsupporting

confidence: 89%

“…This indicates that XaXiY is the inactivation pattern that results in a cell with the preferred dosage of X-linked genes. This observation is supported by previous in vivo experiments, examining XCI in mouse XXY and XXX triploid 10 dpc (days post coitum ) embryos, which showed that 83% of the cells were XaXiY, and 92% of the cells were XaXiXi, respectively [21]. Therefore, we conclude that mouse triploid cells preferably keep only one of their X chromosomes active.…”

Section: Discussionsupporting

confidence: 89%

“…In these experiments cultured differentiated cells were examined which had completed the XCI process [17], and indicated that the majority of cell lines derived from human live born XXX triploids predominantly show two active X chromosomes [18]–[20]. In contrast, analysis of 10-day-old XXY and XXX mouse triploid embryos showed that most cells had one active X chromosome [21]. Unfortunately, both studies did not discriminate between primary choice in XCI and the effect of cell selection processes on XCI.…”

Section: Introductionmentioning

confidence: 99%

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The Probability to Initiate X Chromosome Inactivation Is Determined by the X to Autosomal Ratio and X Chromosome Specific Allelic Properties

et al. 2009

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BackgroundIn female mammalian cells, random X chromosome inactivation (XCI) equalizes the dosage of X-encoded gene products to that in male cells. XCI is a stochastic process, in which each X chromosome has a probability to be inactivated. To obtain more insight in the factors setting up this probability, we studied the role of the X to autosome (X∶A) ratio in initiation of XCI, and have used the experimental data in a computer simulation model to study the cellular population dynamics of XCI.Methodology/Principal FindingsTo obtain more insight in the role of the X∶A ratio in initiation of XCI, we generated triploid mouse ES cells by fusion of haploid round spermatids with diploid female and male ES cells. These fusion experiments resulted in only XXY triploid ES cells. XYY and XXX ES lines were absent, suggesting cell death related either to insufficient X-chromosomal gene dosage (XYY) or to inheritance of an epigenetically modified X chromosome (XXX). Analysis of active (Xa) and inactive (Xi) X chromosomes in the obtained triploid XXY lines indicated that the initiation frequency of XCI is low, resulting in a mixed population of XaXiY and XaXaY cells, in which the XaXiY cells have a small proliferative advantage. This result, and findings on XCI in diploid and tetraploid ES cell lines with different X∶A ratios, provides evidence that the X∶A ratio determines the probability for a given X chromosome to be inactivated. Furthermore, we found that the kinetics of the XCI process can be simulated using a probability for an X chromosome to be inactivated that is proportional to the X∶A ratio. These simulation studies re-emphasize our hypothesis that the probability is a function of the concentration of an X-encoded activator of XCI, and of X chromosome specific allelic properties determining the threshold for this activator.ConclusionsThe present findings reveal that the probability for an X chromosome to be inactivated is proportional to the X∶A ratio. This finding supports the presence of an X-encoded activator of the XCI process.

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“…The X ΔTsix X chromosome offered a sensitized background in which to assess the impact of Xist RNA on X-linked gene silencing, because Xist is ectopically induced from the active X ΔTsix in the epiblast lineage of both males and females. We found that a higher frequency of X ensuring that only one X remains active per diploid genome (47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 88%

Sex-specific silencing of X-linked genes by Xist RNA

Gayen

Maclary

Hinten

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of X ΔTsix Y male cells displayed ectopic Xist RNA coating compared with X ΔTsix X female cells. This increase reflected the inability of X ΔTsix Y cells to efficiently silence X-linked genes compared with X ΔTsix X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X ΔTsix X female cells relative to X ΔTsix Y male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating X ΔTsix Y and 39,X ΔTsix (X ΔTsix O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sexspecific differences. Because X ΔTsix X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X ΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing.inactivation represents a paradigm of epigenetic regulation and long noncoding RNA (lncRNA) function. In XX female cells, one of the two X chromosomes undergoes transcriptional silencing (1). Moreover, replicated copies of the active and inactive X chromosomes faithfully maintain their respective transcriptional states through many cell division cycles (2-5).X inactivation requires the X-inactive specific transcript (Xist) (6-8), a lncRNA that is selectively expressed from and physically coats the future inactive X chromosome (9-12). Xist RNA enables X-linked gene silencing by recruiting protein complexes to the inactive X (13-15). Female mouse embryos that inherit a paternal Xist mutation die due to defects in imprinted X inactivation of the paternal X chromosome in extraembryonic tissues (8,16,17). Xist is also required in the epiblast-derived embryonic cells, which undergo random X inactivation of either the maternal or the paternal X chromosome. Xist heterozygote fetal cells exhibit inactivation of only the X chromosome with an intact Xist locus, suggesting that Xist is necessary to choose the X chromosome to be inactivated (7,18,19). That the Xist-mutant X chromosome is not selected for inactivation, however, precludes assigning to Xist RNA a gene silencing role in the epiblast lineage.Ectopic expression studies have, however, demonstrated that Xist RNA can silence genes, albeit in a context-...

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The pattern of X-chromosome inactivation in the embryonic and extra-embryonic tissues of post-implantation digynic triploid LT/Sv strain mouse embryos

Cited by 9 publications

References 26 publications

The differential staining pattern of the X chromosome in the embryonic and extraembryonic tissues of postimplantation homozygous tetraploid mouse embryos

The differential staining pattern of the X chromosome in the embryonic and extraembryonic tissues of postimplantation homozygous tetraploid mouse embryos

The Probability to Initiate X Chromosome Inactivation Is Determined by the X to Autosomal Ratio and X Chromosome Specific Allelic Properties

Sex-specific silencing of X-linked genes by Xist RNA

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