Effect of polyamine limitation on DNA synthesis and development of mouse preimplantation embryos in vitro

Zwierzchowski, L.; Czlonkowska, M.; Guszkiewicz, A.

doi:10.1530/jrf.0.0760115

Cited by 20 publications

(10 citation statements)

References 13 publications

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“…In vertebrates, there is little evidence for a developmental role for ODC other than inhibitor studies. For example, in vitro depletion of spermine and spermidine by an inhibitor of S-adenosyl-L-methionine decarboxylase arrests growth before the eight-cell or morula stage of fertilized murine embryos, whereas DFMO, a potent inhibitor of ODC, arrests development at the morula-to-blastocyst transition (54). Furthermore, chicken embryos injected with DFMO have marked reductions in their polyamine levels and fail to develop past gastrulation (22).…”

Section: Discussionmentioning

confidence: 99%

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

Pendeville

Carpino²,

Marine

et al. 2001

Molecular and Cellular Biology

229

176

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Overexpression and inhibitor studies have suggested that the c-Myc target gene for ornithine decarboxylase (ODC), the enzyme which converts ornithine to putrescine, plays an important role in diverse biological processes, including cell growth, differentiation, transformation, and apoptosis. To explore the physiological function of ODC in mammalian development, we generated mice harboring a disrupted ODC gene. ODC-heterozygous mice were viable, normal, and fertile. Although zygotic ODC is expressed throughout the embryo prior to implantation, loss of ODC did not block normal development to the blastocyst stage. Embryonic day E3.5 ODCdeficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter. Surprisingly, analysis of ODC-deficient blastocysts suggests that loss of ODC does not affect cell growth per se but rather is required for survival of the pluripotent cells of the inner cell mass. Therefore, ODC plays an essential role in murine development, and proper homeostasis of polyamine pools appears to be required for cell survival prior to gastrulation.Overexpression of the c-Myc, N-Myc, or L-Myc members of the Myc oncogene family is a common event in human tumors. This selection likely reflects Myc's ability to provide continuous proliferative and angiogenic signals under growth-limiting conditions, such as those that occur in the tumor microenvironment (38). However, Myc's propensity to induce continuous proliferation also blocks terminal differentiation (11) and triggers the apoptotic program (2). c-Myc is a basic helix-loophelix leucine zipper protein that exhibits sequence-specific DNA binding to CACGTG or CACATG elements when dimerized with its obligate basic helix-loop-helix leucine zipper partner Max (8). Despite Myc's well-defined function as a transcriptional transactivator, the numbers of its ascribed targets that have been proven to be direct are relatively few, but they do include ornithine decarboxylase (ODC) (6), ␣-prothymosin (15), eIF-4E (44), carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) (28), a DEAD box-related gene (MrDb) (20), the ubiquitin E2 ligase Cul1 (32), and ECA39 (7). A compelling example of a target gene that contributes to c-Myc's biological effects is ODC (34, 35), which is activated by growth factors and by c-Myc through two conserved CACGTG sites present in the first intron of vertebrate ODC genes (6). ODC is the key regulator of the polyamine biosynthetic pathway and decarboxylates L-ornithine to form putrescine (50). ODC expression is highly regulated by changes in its transcription, translation, and RNA and protein half-life (40). Furthermore, ODC enzyme activity is tightly controlled and shows biphasic induction during late G 1 and at G 2 /M (5). Inhibition of ODC by difluoromethylornithine (DFMO) compromises cell growth and transformation (3) and induces cell cycle arrest in G 1 (35,43). ODC inhibition results in marked reductions in the intracellular levels of th...

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Section: Discussionmentioning

confidence: 99%

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

Pendeville

Carpino²,

Marine

et al. 2001

Molecular and Cellular Biology

229

176

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“…Implantation sites in the mouse display elevated levels of expression of Odc1 and polyamines (Zhao et al, 2008). Blockade of Odc1 conversion of ornithine to the polyamine putrescine by the suicide inhibitor difluoromethyl ornithine (DFMO) prevents implantation in the mouse (Zhao et al, 2008) and reversibly arrests development in mink (Lefevre et al, 2011b) and mouse (Zwierzchowski et al, 1986) embryos. Expression of ODC1, along with the polyamine availability genes (Lefevre et al, 2011a) and uterine content of the polyamine putrescine (Lefevre et al, 2011b), are upregulated at the termination of diapause in the mink (Murphy, 2012).…”

Section: The Uterus Dictates Diapausementioning

confidence: 99%

Embryonic diapause: development on hold

Fenelon

Banerjee²,

Murphy³

2014

Int. J. Dev. Biol.

116

130

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Embryonic diapause, the temporary suspension of development of the embryo, is a fascinating reproductive strategy that has been frequently exploited across the animal kingdom. It is characterized by an arrest in development that occurs at the blastocyst stage in over 130 species of mammals. Its presumed function is to uncouple mating from parturition, to ensure that both occur at the most propitious moment for survival of the species. Diapause can be facultative, i.e. induced by physiological conditions, or obligate, i.e. present in every gestation of a species. In the latter case, the proximal signals for regulation are related to photoperiod. Three diverse models, the mouse, the mustelid carnivores and the wallaby have been studied in detail. From these studies it can be discerned that, although the endocrine cues responsible for induction of diapause and re-initiation of development vary widely between species, there are a number of commonalities. Evidence to date indicates that the uterus exercises the proximal regulatory influence over whether an embryo enters into and when it exits from diapause. Some factors have been identified that appear crucial to this regulation, in particular, the polyamines. Recent studies indicate that diapause can be induced in species where it does not exist in nature. This suggests that the potential for diapause in mammals to be due to a single evolutionary event, to which control mechanisms adapted when the trait was beneficial to reproductive success. Further work at the molecular, cellular and organismic levels will be required before the physiological basis of diapause is resolved.

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“…Studies employing inhibitors of polyamine biosynthesis have indicated that an inhibition of ODC will arrest murine embryonic development at the morula‐blastocyst stage and an inhibition of AdoMetDC at an even earlier stage [136]. Moreover, DFMO induces resorption of murine embryos when given just after the first week of gestation [137,138].…”

Section: Odcmentioning

confidence: 99%

“…AdoMetDC‐deficient embryos developed normally to the blastocyst stage, but died shortly thereafter or during the early stage of gastrulation at the latest. They developed distinctly further than did embryos cultured in the presence of an inhibitor of AdoMetDC, methylglyoxal bis(guanylhydrazone) [136]. When cultured in vitro , AdoMetDC‐deficient blastocysts showed an absolute growth requirement for spermidine [142].…”

Section: Adometdcmentioning

confidence: 99%

“…This was apparently due to marked apoptosis occurring in the pluripotent cells of the inner cell mass shown as substantial DNA breakage [139]. The fact that ODC-deficient embryos developed to the blastocyst stage, i.e., to more advanced stage than those grown in vitro in the presence of DFMO [136], was in all likelihood attributable to maternal components [139]. Attempts to rescue the embryos through supplementation of the pregnant females with putrescine were unsuccessful, apparently due to the toxicity of the diamine (high diamine oxidase activity).…”

Section: Odcmentioning

confidence: 99%

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Genetic approaches to the cellular functions of polyamines in mammals

Jänne

Alhonen

Pietilä

et al. 2004

European Journal of Biochemistry

183

146

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The polyamines putrescine, spermidine and spermine are organic cations shown to participate in a bewildering number of cellular reactions, yet their exact functions in intermediary metabolism and specific interactions with cellular components remain largely elusive. Pharmacological interventions have demonstrated convincingly that a steady supply of these compounds is a prerequisite for cell proliferation to occur. The last decade has witnessed the appearance of a substantial number of studies, in which genetic engineering of polyamine metabolism in transgenic rodents has been employed to unravel their cellular functions. Transgenic activation of polyamine biosynthesis through an overexpression of their biosynthetic enzymes has assigned specific roles for these compounds in spermatogenesis, skin physiology, promotion of tumorigenesis and organ hypertrophy as well as neuronal protection. Transgenic activation of polyamine catabolism not only profoundly disturbs polyamine homeostasis in most tissues, but also creates a complex phenotype affecting skin, female fertility, fat depots, pancreatic integrity and regenerative growth. Transgenic expression of ornithine decarboxylase antizyme has suggested that this unique protein may act as a general tumor suppressor. Homozygous deficiency of the key biosynthetic enzymes of the polyamines, ornithine and S-adenosylmethionine decarboxylase, as achieved through targeted disruption of their genes, is not compatible with murine embryogenesis. Finally, the first reports of human diseases apparently caused by mutations or rearrangements of the genes involved in polyamine metabolism have appeared.Keywords: antizyme; ornithine decarboxylase; putrescine; spermidine/spermine N 1 -acetyltransferase; spermidine; spermine; transgenic mouse; transgenic rat. IntroductionThe cellular functions of the natural polyamines (putrescine, spermidine and spermine) are still largely unknown, although a vast number of studies have shown that these polycationic compounds are crucial to the growth and proliferation of mammalian cells. Pharmacological approaches are applied typically in studies aimed to unravel their functions in cellular metabolism and, admittedly, much valuable information has been generated with the use of specific inhibitors of polyamine biosynthesis. However, the last decade has produced a substantial number of experimental studies in which genetic engineering of polyamine metabolism has been used as a tool to elucidate their cellular functions. Studies with genetically engineered mice and rats have not only brought entirely new information about the involvement of polyamines in various physiological and pathophysiological processes but they have likewise challenged some of the conventional wisdoms. Mainly, four different approaches have been applied in the genetic engineering of experimental animals: (a) activation of polyamine biosynthesis through the overexpression of their biosynthetic enzymes; (b) activation of polyamine catabolism through the overexpression of the enzymes i...

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Effect of polyamine limitation on DNA synthesis and development of mouse preimplantation embryos in vitro

Abstract: Summary. In-vitro treatment of preimplantation mouse embryos with spermine and spermidine biosynthesis inhibitor, methylglyoxal-bis-(guanylhydrazone) (MGBG)

Cited by 20 publications

References 13 publications

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

Embryonic diapause: development on hold

Genetic approaches to the cellular functions of polyamines in mammals

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