The developmental analysis of an embryonic lethal (C6H) in the mouse.
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A development study of the effects of the C6H allele at the albino locus has identified the C6H homozygote as an early postimplantation lethal. Homozygous C6H embryos can first be recognized at 6 1/2-7 days of gestation by abnormalities of the ectoplacental and parietal endodern. At 7 1/2 days, mutant embryos appear severely retarded with obvious abnormalities in all germ layers. All C6H homozygotes are dead and resorbed by 8 days of development. It is proposed that the mutation interferes with the normal differentiation of the parietal endoderm, ectoplacental cone and extra-embryonic ectoderm of the egg cyclinder. (+info)
Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid.
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Targeting of mouse alcohol dehydrogenase genes Adh1, Adh3, and Adh4 resulted in null mutant mice that all developed and reproduced apparently normally but differed markedly in clearance of ethanol and formaldehyde plus metabolism of retinol to the signaling molecule retinoic acid. Following administration of an intoxicating dose of ethanol, Adh1 -/- mice, and to a lesser extent Adh4 -/- mice, but not Adh3 -/- mice, displayed significant reductions in blood ethanol clearance. Ethanol-induced sleep was significantly longer only in Adh1 -/- mice. The incidence of embryonic resorption following ethanol administration was increased 3-fold in Adh1 -/- mice and 1.5-fold in Adh4 -/- mice but was unchanged in Adh3 -/- mice. Formaldehyde toxicity studies revealed that only Adh3 -/- mice had a significantly reduced LD50 value. Retinoic acid production following retinol administration was reduced 4.8-fold in Adh1 -/- mice and 8.5-fold in Adh4 -/- mice. Thus, Adh1 and Adh4 demonstrate overlapping functions in ethanol and retinol metabolism in vivo, whereas Adh3 plays no role with these substrates but instead functions in formaldehyde metabolism. Redundant roles for Adh1 and Adh4 in retinoic acid production may explain the apparent normal development of mutant mice. (+info)
Interaction of late pregnancy and lactation in rats.
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The effect of pregnancy on lactation was studied during the third week of lactational pregnancy in postpartum pregnant rats with a delay in implantation of only 1 day (1d-LP rats). In an experimental design in which the suckling litter was prevented from consuming solid food, lactational performance was estimated by weighing the ten-pup suckling litters on days 16-21 of lactation or by measuring maternal weight loss after a nursing spell on day 21. In 1d-LP rats, food consumption as well as lactational performance was lower than it was in nonpregnant lactating rats (L rats) and pregnant-lactating rats with a normal long delay of implantation of at least 6 days (LP rats). The time spent by the pups sucking at the nipples was not different among the three groups, but the number of milk ejections was diminished in 1d-LP dams. Restriction of daily food supply during days 16 to 21 of lactation diminished lactational performance more strongly in 1d-LP rats than it did in L rats; 1d-LP rats conserved protein stores and mobilized fewer minerals than did L rats. The weight and composition of the litter in vitro were not affected by the food restriction. In pregnant-lactating rats (LP and 1d-LP rats), the number of early resorptions was increased in comparison with pregnant rats, showing that lactation can affect the earlier stages of pregnancy. It was concluded that late pregnancy does not affect nursing behaviour, but suppresses lactation by restricting maternal food intake and mobilization of maternal stores. Measurements in serum indicate a causative role for oestradiol, but not for leptin. (+info)
A null mutation in the inflammation-associated S100 protein S100A8 causes early resorption of the mouse embryo.
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S100A8 (also known as CP10 or MRP8) was the first member of the S100 family of calcium-binding proteins shown to be chemotactic for myeloid cells. The gene is expressed together with its dimerization partner S100A9 during myelopoiesis in the fetal liver and in adult bone marrow as well as in mature granulocytes. In this paper we show that S100A8 mRNA is expressed without S100A9 mRNA between 6.5 and 8. 5 days postcoitum within fetal cells infiltrating the deciduum in the vicinity of the ectoplacental cone. Targeted disruption of the S100A8 gene caused rapid and synchronous embryo resorption by day 9. 5 of development in 100% of homozygous null embryos. Until this point there was no evidence of developmental delay in S100A8-/- embryos and decidualization was normal. The results of PCR genotyping around 7.5-8.5 days postcoitum suggest that the null embryos are infiltrated with maternal cells before overt signs of resorption. This work is the first evidence for nonredundant function of a member of the S100 gene family and implies a role in prevention of maternal rejection of the implanting embryo. The S100A8 null provides a new model for studying fetal-maternal interactions during implantation. (+info)
Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification.
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Genetic and molecular evidence indicates that visceral endoderm, an extraembryonic cell lineage, is required for gastrulation, early anterior neural patterning, cell death and specification of posterior mesodermal cell fates. We show that variant Hepatocyte Nuclear Factor 1 (vHNF1), a homeodomain-containing transcription factor first expressed in the primitive endoderm, is required for the specification of visceral endoderm. vHnf1-deficient mouse embryos develop normally to the blastocyst stage, start implantation, but die soon afterwards, with abnormal or absent extraembryonic region, poorly organised ectoderm and no discernible visceral or parietal endoderm. However, immunostaining analysis of E5.5 nullizygous mutant embryos revealed the presence of parietal endoderm-like cells lying on an abnormal basal membrane. Homozygous mutant blastocyst outgrowths or differentiated embryonic stem cells do not express early or late visceral endoderm markers. In addition, in vHnf1 null embryoid bodies there is no activation of the transcription factors HNF-4alpha1, HNF1alpha and HNF-3gamma. Aggregation of vHnf1-deficient embryonic stem cells with wild-type tetraploid embryos, which contribute exclusively to extraembryonic tissues, rescues periimplantation lethality and allows development to progress to early organogenesis. Our results place vHNF1 in a preeminent position in the regulatory network that specifies the visceral endoderm and highlight the importance of this cell lineage for proper growth and differentiation of primitive ectoderm in pregastrulating embryos. (+info)
Reduced survival after human embryo biopsy and subsequent cryopreservation.
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Preimplantation genetic diagnosis (PGD) is performed in couples at risk of genetic disease, so as to avoid transfer of embryos which are affected by a monogenic disease or which carry chromosomal aberrations. As in all in-vitro fertilization (IVF) cycles, supernumerary non-affected good-quality embryos may be available after PGD. These embryos can be cryopreserved. So far, limited data on survival after cryopreservation of biopsied human embryos are available. In this study, human embryos of good morphological quality derived from abnormal fertilization were used to evaluate the influence of the embryo biopsy procedure on survival after cryopreservation. Embryos were allocated to three different groups: control (n = 20), drilling-only (n = 16), and biopsy (n = 29). After freezing and thawing, a significantly lower number of blastomeres was intact in the drilling-only group (46/118, i.e. 39.0%, P < 0.01) and in the embryo biopsy group (46/156, i.e. 29.5%, P < 0.0001) than in the control group (85/151, i.e. 56.3%). This difference was reflected in survival rates of embryos. Fifty-five per cent of the control embryos, 37.5% of the drilling-only group, and 33.3% of the biopsy group had at least 50% of their blastomeres intact. After further in-vitro culture, four blastocysts, three from the drilling-only group and one from the biopsy group, developed from the surviving embryos. From this study it can be concluded that current cryopreservation procedures are less successful when biopsied human embryos are cryopreserved, but that surviving embryos can develop to the blastocyst stage and thus may have the potential to develop to term. (+info)
Targeted disruption of the gene encoding the proteolipid subunit of mouse vacuolar H(+)-ATPase leads to early embryonic lethality.
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Vacuolar H(+)-ATPase (V-ATPase) is responsible for acidification of intracellular compartments in eukaryotic cells. Its 16-kDa subunit (proteolipid, PL16) plays a central role in V-ATPase function, forming the principal channel via which protons are translocated. To elucidate physiological roles of V-ATPase in mammalian cell function and embryogenesis, we attempted to generate a PL16 null mutant mouse by gene-targeting. Mice heterozygous (PL16(+/-)) for the proteolipid mutation were intercrossed and their offspring were classified according to genotype. There were no homozygous (PL16(-/-)) pups among 69 neonates examined, but a few PL16(-/-) embryos were found during the pre-implantation stages of embryonic development, up to day 3.5 post-coitum. These results suggested that PL16 (and hence V-ATPase) may play an essential role in cell proliferation and viability during early embryogenesis. PL16(+/-) mice were indistinguishable from their wild-type littermates and displayed no discernible abnormalities, although the PL16 mRNA level in PL16(+/-) mice decreased to about one-half of wild-type levels. (+info)
Protective effects of garlic juice against embryotoxicity of methylmercuric chloride administered to pregnant Fischer 344 rats.
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In order to investigate the beneficial effects of 0.5 or 1.0 g/kg Korean garlic juice against the embryotoxicity of 20 mg/kg methylmercury chloride (MMC, CH3HgCl), pregnant Fisher 344 rats were simultaneously orally administered on day 7 of gestation. On day 20 of gestation the dams were laparotomized under ether anesthesia, and the fetuses were removed and examined for toxicity of methylmercury. Garlic juice depressed the toxicity in terms of some parameters. In the case of simultaneous treatment with 0.1 g/kg garlic juice and MMC, rates of increase were 17.5% in maternal body weight, 13.2% and 41.9% in fetal and litters' weight respectively, and 37.0% in fetal survival rate. Decreasing rates were 10.0% in maternal death rate, and 6.9% and 31.3% in pre- and post-implantation loss respectively. Decreasing rates of mercury levels in dams were 67.2% in liver, 57.6% in brain, 47.2% in kidney, 42.1% in spleen and 40.9% in blood. As well, decreasing rates of mercury level in fetuses were 54.9% in all body burden, 55.9% in liver, 46.7% in kidney and 37% in brain, respectively. The number of fetal ossification centers were reduced by 23.8% to 58.0% following simultaneous treatment with 1.0 g/kg garlic juice. These findings indicated that garlic juice effectively inhibited the embryotoxicity of methylmercury in pregnant Fischer 344 rats. (+info)