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PubMed1986

Age-related changes in ploidy levels and biochemical parameters in cardiac myocytes isolated from spontaneously hypertensive rats.

Postnatal growth of the mammalian ventricular myocyte is characterized by a brief period of hyperplasia followed by an extensive period of physiological hypertrophy. Using myocytes isolated from both Wistar-Kyoto and spontaneously hypertensive rats from fetus to 10 months old, we analyzed morphological, biochemical, and ploidy changes. Fetal myocytes from both spontaneously hypertensive and Wistar-Kyoto rats were mononuclear, diploid cells. By 4 weeks, adult binucleation levels (84% binuclear) were found, and myocytes pooled from both ventricles demonstrated nuclear ploidy shifts to tetraploid levels. However, analysis of myocytes isolated from left ventricle, right ventricle, and septum showed that nuclear polyploidation was confined to the right ventricle and septum, with few polyploid nuclei detected in the left ventricle. This pattern remained relatively constant through 10 months of age, although spontaneously hypertensive myocytes showed significantly more polyploidation than Wistar-Kyoto in all regions. Biochemical analysis of isolated myocytes substantiated the nuclear ploidy changes and demonstrated elevated protein and ribonucleic acid content in left ventricular myocytes without extensive polyploidation. Since cardiac hypertrophy, both physiological and pathological, is associated primarily with the left ventricle and occurs in the absence of significant ploidy changes, these findings suggest that a unique pattern of gene regulation may be ongoing in the left ventricle myocytes that is not present in the septum and right ventricle. These variations may be essential for cellular hypertrophy under normal and pathological conditions.

Aging↗
PubMed2005

Euploidy in somatic cells from R6/2 transgenic Huntington's disease mice.

BACKGROUND: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. The huntingtin protein expressed from HD has an unknown function but is suggested to interact with proteins involved in the cell division machinery. The R6/2 transgenic mouse is the most widely used model to study HD. In R6/2 fibroblast cultures, a reduced mitotic index and high frequencies of multiple centrosomes and aneuploid cells have recently been reported. Aneuploidy is normally a feature closely connected to neoplastic disease. To further explore this unexpected aspect of HD, we studied cultures derived from 6- and 12-week-old R6/2 fibroblasts, skeletal muscle cells, and liver cells. RESULTS: Cytogenetic analyses revealed a high frequency of polyploid cells in cultures from both R6/2 and wild-type mice with the greatest proportions of polyploid cells in cultures derived from skeletal muscle cells of both genotypes. The presence of polyploid cells in skeletal muscle in vivo was confirmed by fluorescence in situ hybridisation with centromeric probes. Enlarged and supernumerary centrosomes were found in cultures from both R6/2 and wild-type mice. However, no aneuploid cells could be found in any of the tissues. CONCLUSION: We conclude that polyploid cells are found in fibroblast and skeletal muscle cultures derived from both R6/2 and wild-type littermate mice and that aneuploidy is unlikely to be a hallmark of HD.

Aneuploidy↗
PubMed1993

Hepatic nuclear ploidy distribution of dietary-restricted mice.

Hepatic parenchymal cells in most adult mammals are polyploid, with most of the cells in the quiescent or low-proliferation state. Polyploidization has been related to carcinogenesis and aging, and both end points are significantly affected by dietary restriction (DR). Direct measures of hepatic nuclear polyploidization in DR B6C3F1 mice have not been examined. We examined the effect of DR on distributions of nuclear ploidy in both sexes and on different age groups of B6C3F1 mice. Differences between young and old male mice and between old male and female mice were also compared. Hepatic nuclear ploidy values were measured by flow cytometry. The DNA histograms were analyzed for the percentage of nuclei having different classes of DNA content by gating channels between the areas under the peaks of diploid, tetraploid, and octaploid. The results indicate that 1 or 26 months of DR started at 4 months of age did not alter hepatic nuclear ploidy distributions in young and old mice. Our data suggest that in the male mouse, polyploidization is established by 5 months of age for hepatic nuclei and that ploidy classes are affected by sex at 30 months of age. For females, effects in the octaploid nuclei are seen as a result of DR.

Age Factors↗
PubMedDate not supplied

Human diploid fibroblast cells in senescence; cycling through polyploidy to mitotic cells.

Previously, it was found that senescent cells can undergo a modified cell cycle with mitotic cells as the end results. The major cycling events started with polyploidization, followed by depolyploidization to multinucleated cells (MNCs). These latter cells produced mononuclear offspring cells that could express mitotic cell divisions. In this report the emphasis is on late senescent fibroblasts that exhibited the senescence-associated change in cell morphology to large flat cells. Prior to live cell photography, flat cell cultures were maintained for months in the same culture flasks and therefore judged to be in a late senescent phase. All of the cellular events outlined above were present in these old cell cultures. Time lapse pictures showed movements of mitotic daughter cells away from each other and alignment of the chromosomes on the metaphase plate was visible in other mitotic cells. These data challenge the common view that cell senescence is irreversible and, therefore, an antitumor mechanism. A new finding was that the spike in polyploid cells in the near senescent phase consisted of cells with pairs of sister chromosomes from endoreduplication of DNA (two rounds of DNA synthesis and no mitosis). The lack of cells with 92 single chromosomes (e.g., G2 tetraploid cells) suggested that these polyploid cells also went through a changed cell cycle. The question now is whether these atypical polyploid cells are a subpopulation in senescence that can undergo the cycling from polyploidy to genome-reduced mitotic cells.

Cell Culture Techniques↗
PubMed2004

Defects arising from whole-genome duplications in Saccharomyces cerevisiae.

Comparisons among closely related species have led to the proposal that the duplications found in many extant genomes are the remnants of an ancient polyploidization event, rather than a result of successive duplications of individual chromosomal segments. If this interpretation is correct, it would support Ohno's proposal that polyploidization drives evolution by generating the genetic material necessary for the creation of new genes. Paradoxically, analysis of contemporary polyploids suggests that increased ploidy is an inherently unstable state. To shed light on this apparent contradiction and to determine the effects of nascent duplications of the entire genome, we generated isogenic polyploid strains of the budding yeast Saccharomyces cerevisiae. Our data show that an increase in ploidy results in a marked decrease in a cell's ability to survive during stationary phase in growth medium. Tetraploid cells die rapidly, whereas isogenic haploids remain viable for weeks. Unlike haploid cells, which arrest growth as unbudded cells, tetraploid cells continue to bud and form mitotic spindles in stationary phase. The stationary-phase death of tetraploids can be prevented by mutations or conditions that result in growth arrest. These data show that whole-genome duplications are accompanied by defects that affect viability and subsequent survival of the new organism.

Evolution, Molecular↗
PubMed2005

A general framework for statistical linkage analysis in multivalent tetraploids.

In multivalent polyploids, simultaneous pairings among homologous chromosomes at meiosis result in a unique cytological phenomenon-double reduction. Double reduction casts an impact on chromosome evolution in higher plants, but because of its confounded effect on the pattern of gene cosegregation, it complicates linkage analysis and map construction with polymorphic molecular markers. In this article, we have proposed a general statistical model for simultaneously estimating the frequencies of double reduction, the recombination fraction, and optimal parental linkage phases between any types of markers, both fully and partially informative, or dominant and codominant, for a tetraploid species that undergoes only multivalent pairing. This model provides an in-depth extension of our earlier linkage model that was built upon Fisher's classifications for different gamete formation modes during the polysomic inheritance of a multivalent polyploid. By implementing a two-stage hierarchical EM algorithm, we derived a closed-form solution for estimating the frequencies of double reduction through the estimation of gamete mode frequencies and the recombination fraction. We performed different settings of simulation studies to demonstrate the statistical properties of our model for estimating and testing double reduction and the linkage in multivalent tetraploids. As shown by a comparative analysis, our model provides a general framework that covers existing statistical approaches for linkage mapping in polyploids that are predominantly multivalent. The model will have great implications for understanding the genome structure and organization of polyploid species.

Algorithms↗
PubMed2006

Genetic map-based analysis of genome structure in the homosporous fern Ceratopteris richardii.

Homosporous ferns have extremely high chromosome numbers relative to flowering plants, but the species with the lowest chromosome numbers show gene expression patterns typical of diploid organisms, suggesting that they may be diploidized ancient polyploids. To investigate the role of polyploidy in fern genome evolution, and to provide permanent genetic resources for this neglected group, we constructed a high-resolution genetic linkage map of the homosporous fern model species, Ceratopteris richardii (n = 39). Linkage map construction employed 488 doubled haploid lines (DHLs) that were genotyped for 368 RFLP, 358 AFLP, and 3 isozyme markers. Forty-one linkage groups were recovered, with average spacing between markers of 3.18 cM. Most loci (approximately 76%) are duplicated and most duplicates occur on different linkage groups, indicating that as in other eukaryotic genomes, gene duplication plays a prominent role in shaping the architecture of fern genomes. Although past polyploidization is a potential mechanism for the observed abundance of gene duplicates, a wide range in the number of gene duplicates as well as the absence of large syntenic regions consisting of duplicated gene copies implies that small-scale duplications may be the primary mode of gene duplication in C. richardii. Alternatively, evidence of past polyploidization(s) may be masked by extensive chromosomal rearrangements as well as smaller-scale duplications and deletions following polyploidization(s).

Chromosome Mapping↗
PubMed2004

Computerized video time lapse study of cell cycle delay and arrest, mitotic catastrophe, apoptosis and clonogenic survival in irradiated 14-3-3sigma and CDKN1A (p21) knockout cell lines.

Computerized video time lapse (CVTL) microscopy was used to observe cellular events induced by ionizing radiation (10-12 Gy) in nonclonogenic cells of the wild-type HCT116 colorectal carcinoma cell line and its three isogenic derivative lines in which p21 (CDKN1A), 14-3-3sigma or both checkpoint genes (double-knockout) had been knocked out. Cells that fused after mitosis or failed to complete mitosis were classified together as cells that underwent mitotic catastrophe. Seventeen percent of the wild-type cells and 34-47% of the knockout cells underwent mitotic catastrophe to enter generation 1 with a 4N content of DNA, i.e., the same DNA content as irradiated cells arrested in G(2) at the end of generation 0. Radiation caused a transient division delay in generation 0 before the cells divided or underwent mitotic catastrophe. Compared with the division delay for wild-type cells that express CDKN1A and 14-3-3sigma, knocking out CDKN1A reduced the delay the most for cells irradiated in G(1) (from approximately 15 h to approximately 3- 5 h), while knocking out 14-3-3sigma reduced the delay the most for cells irradiated in late S and G(2) (from approximately 18 h to approximately 3-4 h). However, 27% of wild-type cells and 17% of 14-3-3sigma(-/-) cells were arrested at 96 h in generation 0 compared with less than 1% for CDKN1A(-/-) and double-knockout cells. Thus expression of CDKN1A is necessary for the prolonged delay or arrest in generation 0. Furthermore, CDKN1A plays a crucial role in generation 1, greatly inhibiting progression into subsequent generations of both diploid cells and polyploid cells produced by mitotic catastrophe. Thus, in CDKN1A-deficient cell lines, a series of mitotic catastrophe events occurred to produce highly polyploid progeny during generations 3 and 4. Most importantly, the polyploid progeny produced by mitotic catastrophe events did not die sooner than the progeny of dividing cells. Death was identified as loss of cell movement, i.e. metabolic activity. Thus mitotic catastrophe itself is not a direct mode of death. Instead, apoptosis during interphase of both uninucleated and polyploid cells was the primary mode of death observed in the four cell types. Knocking out either CDKN1A or 14-3-3sigma increased the amount of cell death at 96 h, from 52% to approximately 70%, with an even greater increase to 90% when both genes were knocked out. Thus, in addition to effects of CDKN1A and 14-3-3sigma expression on transient cell cycle delay, CDKN1A has both an anti-proliferative and anti-apoptosis function, while 14-3-3sigma has only an anti-apoptosis function. Finally, the large alterations in the amounts of cell death did not correlate overall with the small alterations in clonogenic survival (dose-modifying ratios of 1.05-1.13); however, knocking out CDKN1A resulted in a decrease in arrested cells and an increase in survival, while knocking out 14-3-3sigma resulted in an increase in apoptosis and a decrease in survival.

14-3-3 Proteins↗
PubMed1992

[Flow cytometric analysis of DNA ploidy in nasosinal papilloma].

Using paraffin embedded specimens taken from 32 patients with histologically benign nasosinal papillomas, we conducted nuclear DNA analysis by flow cytometry and studied the biological degree of malignancy in this disease. Aneuploidy, which is frequently observed in malignant tumors was not seen in any of these nasosinal papilloma cases. Age did not affect either S+G2M % or polyploid %, two parameters that reflect cell proliferation capacity. Both parameters, S+G2M % and polyploid %, were higher in inverted papillomas which are more likely to become malignant than epithelial papillomas. In recurrent cases of nasosinal papilloma both S+G2M % and polyploid % were higher than in nonrecurrent cases. Moreover, the polyploid % was significantly different, supporting speculation that this can be used as a parameter for predicting recurrence of nasosinal papilloma.

Cell Nucleus↗
PubMed2005

Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation.

Physiological polyploidy is a characteristic of several cell types including the megakaryocytes (MK) that give rise to circulating blood platelets. MK achieve polyploidy by switching from a normal to an endomitotic cell cycle characterized by the absence of late mitotic stages. During an endomitotic cycle, the cells enter into mitosis and proceed normally through metaphase and early anaphase. However, late anaphase, telophase and cytokinesis are aborted. This abortive mitosis is associated with atypical multipolar mitotic spindles and limited chromosome segregation. Stathmin is a microtubule-depolymerizing protein that is important for the regulation of the mitotic spindle and interfering with its expression disrupts the normal mitotic spindle and leads to aberrant mitotic exit. As cells enter mitosis, the microtubule depolymerizing-activity of stathmin is switched-off, allowing microtubules to polymerize and assemble into a mitotic spindle. Reactivation of stathmin in the later stages of mitosis is necessary for the disassembly of the mitotic spindle and the exit from mitosis. Previous studies had shown that stathmin expression is downregulated as MK become polyploid and inhibition of its expression in K562 cells increases their propensity to become polyploid. In this report, we describe our studies of the mechanism by which stathmin plays its role in MK polyploidization. We show that stathmin overexpression prevents the transition from a mitotic cycle to an endomitotic cycle as determined by a decrease in the number of multipolar mitotic spindles. These observations support a model in which downregulation of stathmin expression in megakaryocytes and other polyploid cells may be a critically important factor in endomitosis and polyploidy.

Cell Differentiation↗
PubMed1994

[Tumor heterogeneity in DNA ploidy of renal cell carcinomas as revealed by static cytofluorometry and flow cytometry].

DNA ploidy of 49 renal cell carcinomas of 46 patients were examined with static cytofluorometry (SCM) and flow cytometry (FCM). We used several paraffin blocks for each tumor (mean, 2.4), separated each block into several samples based on histological findings, and measured the DNA content of each sample. More samples could be analyzed with SCM than with FCM. With FCM, it was sometimes difficult to detect polyploid cells, or to determine whether diploid cells were tumor cells or stromal cells. DNA heterogeneity might thus be more accurately detected with SCM than with FCM. DNA aneuploidy was demonstrated for 59% of the tumors, and was significantly less common in grade 1 tumors than in higher-grade tumors. The incidence of polyploid cells in diploid tumors tended to increase with grade of tumor. Fifty-five percent of the tumors displayed DNA heterogeneity, the incidence of which tended to increase with grade of tumor. Ninety-four percent of the tumors were found to yield a diploid cell line. The findings of this study indicate that DNA content is associated with the histological grading. Diploid tumors with polyploid cells should be dealt with clinically in a separate fashion from diploid tumors without them. These findings suggest that diploid renal cell carcinomas with polyploid cells may be an intermediate stage between diploidy and aneuploidy.

Aneuploidy↗
PubMedDate not supplied

DNA cytofluorometric analysis of benign and malignant nerve sheath tumors.

The present study was undertaken to examine the ploidy patterns of benign and malignant nerve sheath tumors using PI-DNA cytofluorometry and to clarify the relationship between the ploidy patterns and pathological findings for these lesions. The benign nerve sheath tumors (schwannomas and neurofibromas) were found to be dipolid or to be euploid-polyploidization, with a few DNA synthetic cells. The number of polyploid cells increased with increase in the frequency of cells with large and atypical nuclei in histology, regardless of the natures of cellular arrangements. Malignant schwannomas were composed of many polyploid and aneuploid cells with DNA synthetic cells, indicating their active cell proliferation. Thus, benign nerve sheath tumors exhibited low-proliferative ploidy patterns that were clearly different from those of malignant nerve sheath tumors. As Takeshita has already stated, it is difficult to ascertain why some of the neurogenic tumors show euploid-polyploidization (19). Further investigations will be needed in this direction. Finally, it is clear from the results of this study that the cytofluorometric analysis mentioned above is useful for assessing malignancy and that it may be useful for predicting prognosis of nerve sheath tumors.

Adolescent↗
PubMed2002

[Somatic polyploidy in neurons of the gastropod mollusca. III. Mitosis and endomitosis in the postnatal development of neurons in the Succinea snail central nervous system].

General morphology of chromatin, the number of chromosomes and chromocenters in normal condition and at the increase of bivalent cation (Ca2+, Mg2+) concentration were studied with the purpose to reveal mechanisms of polyploidization of neuron nuclei in the snail Succinea lauta (Gastropoda, Pulmonata). The morphology of nuclei was studied on squashed preparations. Normal diploid mitoses are described in the cerebral ganglia. A possibility is supposed that part of neurons or neuroblasts in the central nervous system (CNS) of succineid snail may divide mitotically. It has been shown that the basic mechanism of neuron postnatal growth is endomitotic polyploidization of nuclei. The transition from ordinary mitosis to polyploid cycles occurs via restitutional (polyploidizing) mitosis (4c2n-->4c4n). The next endocycles are carried out by means of classic endomitosis up to reaching the highest ploidy levels--4096n--16,384n. The study of general morphology of chromatin and chromocenters at normal condition and at artificial compactization enabled us to exclude any probability of polyteny in the CNS of lauta.

Animals↗
PubMed1992

[Microspectrophotometric analysis of DNA content in duct epithelial proliferation and invasive carcinoma of the pancreas].

Nuclear DNA content of 131 pancreatic duct epithelial lesions, including 10 normal ducts, 30 intraductal proliferations with mild atypia (groups I-II), 30 with moderate atypia (group III), 24 with severe atypia (group IV), 14 of carcinoma in situ (group V), and 23 invasive carcinomas, was analyzed using microspectrophotometry. DNA histograms were classified into diploid, polyploid and aneuploid patterns. All of normal duct epithelia showed diploidy. Polyploid patterns were observed in 3 (10%) lesions of groups I-II, 17 (56.7%) of group III, 14 (58.4%) of group IV, 7 (50%) of group V, and 6 (26.1%) of invasive carcinomas, and aneuploid patterns were observed in 0%, 10%, 33.3%, 50% and 73.9%, respectively. This distribution of ploidy patterns revealed a gradual shift to the main ploidy from diploid to polyploid followed by aneuploid in proportion to the increase of the degree of epithelial atypia. The frequencies of polyploid cells in each lesion were determined. Their averages were 0.2% in groups I-II, 1.9% in group III, 3.4% in group IV, 4.4% in group V, and 6.7% in invasive carcinoma. The S+G2M phase fractions were significantly higher in proliferative epithelia than in normal. The results of this study suggest that duct epithelial proliferations of the pancreas have "genetic instability" leading to a serial clonal evolution and play a significant role in the progression of pancreatic duct cell carcinoma.

Carcinoma in Situ↗
PubMed2005

Association of ploidy and sexual system in Lycium californicum (Solanaceae).

In North American Lycium (Solanaceae), the evolution of gender dimorphism has been proposed as a means of restoring outcrossing after polyploidization causes the loss of self-incompatibility. Previous studies of this process in Lycium focused on comparisons between species that differ in ploidy. We examined intraspecific variation in floral morphology and DNA content in populations of L. californicum to determine correlations between sexual system and cytotype. We also used nuclear ITS and GBSSI sequence data to determine whether diploid and polyploid forms represent the same phylogenetic species, and the phylogeographic relationships among populations and ploidy levels. Within populations, no variation in ploidy was found, although among populations there was a perfect correspondence between sexual system and cytotype. Diploid populations were all hermaphroditic, whereas tetraploid populations were all gender dimorphic. There was no clear geographic pattern to the occurrence of diploid and tetraploid forms. Phylogenetic analysis confirms that L. californicum, regardless of ploidy, forms a monophyletic group within the genus Lycium. Sequences from diploid and polyploid individuals did not form reciprocally monophyletic clades, indicating either multiple gains of polyploidy, ongoing gene flow between cytotypes, or lack of lineage sorting since the evolution of polyploidy. The correspondence between ploidy and sex expression is consistent with the hypothesis that polyploidization triggers the evolution of gender dimorphism in this and other Lycium species.

Arizona↗
PubMed1991

[Proliferation of smooth muscle cells in hypertension].

The aortic intima and media isolated from hypertensives showed a significantly larger number (up to 20%) of smooth muscle cells (SMC) with tetraploid DNA content. The similar process was shown to be also a part of normal human vessel maturation. Normotensive human and rat aortic SMCs were found to accumulate 3H-thymidine, have a lower proliferative ability and they were apt to polyploidize in the primary culture. Such a population could not be detected in the aorta of spontaneously hypertensive rats. It was ascertained that 10 microM of noradrenaline significantly increased (approximately by 2 times) the occurrence of true polyploid cells in the rat aortic SMC subculture. The effect of noradrenaline was blocked by the concomitant effects of alpha- and beta-adrenoreceptor antagonists. SMC polyploidization was also stimulated by the simultaneously use of the direct activators of second messenger systems forskolin and phorbol-12-myristate-13-acetate. Thus, the SMC subpopulation that is apt to polyploidize exists in normal vessels and noradrenaline may be one of the mediators of a response of the vascular wall SMC, which seems to occur due to the synergism of two second messenger systems.

Animals↗
PubMed1991

[Nuclear DNA analysis of benign skin tumor and carcinoma in site developed from keratinocyte].

To know the variation of DNA contents of seborrheic keratosis, keratoacanthoma, actinic keratosis, and Bowen's disease, cytophotometric assay was used. As the results, following findings were obtained. 1. DNA index of actinic keratosis was higher than those of seborrheic keratosis and keratoacanthoma. 2. DNA index of Bowen's disease was higher than that of seborrheic keratosis. 3. Polyploid cell population (greater than 6C) of keratoacanthoma was higher than that of seborrheic keratosis. 4. Polyploid cell populations (greater than GC) of carcinoma in site (actinic keratosis, Bowen's disease) were higher than that of keratoacanthoma . These date suggested that polyploid cell population and DNA index reflect grade of malignancy of tumor developed from keratinocytes. A clinic keratosis and Bowen's disease revealed almost the same DNA pattern. And the difference of polyploid cell population of keratoacanthoma++ ++ and seborrheic keratosis suggested the difference of the biological activity of them.

Aged↗
PubMedDate not supplied

[Similarities and differences in the growth of the heart in situ and in transplants].

Growth and ploidy of rat ventricular myocytes were studied during development in situ and in grafts (1 day old rat ventricle transplanted under kidney capsule of syngenic adult animals). Both in situ and in the transplants polyploidization occurred on days 4-14 of postnatal life, and the modal group of myocytes was represented by binucleate diploid (2c x 2) cells. Minor quantities of 4c, 4c x 2, 8c and 2c x 4 myocytes were detected as well. In ventricles of 14 and 28 days old rats and in the transplants of the corresponding age the portion of polyploid myocytes was 90-96% and 32-63% respectively. The intensity of postmitotic myocyte transplants was decreased as compared with in situ development, and cells that exit proliferation cycle did not grow until day 14. The data on thymidine label dilution suggest that diploid myocytes of the transplant can divide two or three times but the majority of labeled diploids divided only once. Labeled 2c x 2 myocytes originated from the first, and less frequently, the second cell generation or resulted from initial acytokinetic mitosis. Mononucleate tetraploids 4c originated from 2c x 2 and mostly from 2c cells. Octaploids were formed after 3d or 4th labeled mitosis. The conclusion about cardiac myocyte polyploidization as an intrinsic developmental program is supported, implying the programming of onset, mode, duration and termination of polyploidization and its prolongation during early postnatal life.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗