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Results for “embryonic lethality”

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PubMed1989

A sperm-supplied product essential for initiation of normal embryogenesis in Caenorhabditis elegans is encoded by the paternal-effect embryonic-lethal gene, spe-11.

Loss-of-function mutations in the spe-11 gene in Caenorhabditis elegans result in a paternal-effect embryonic-lethal phenotype: fertilization of wild-type oocytes by sperm from homozygous spe-11 mutant males leads to abnormal zygotic development, whereas oocytes from homozygous spe-11 hermaphrodites when fertilized by wild-type sperm develop normally. Embryos fertilized by sperm from homozygous spe-11 worms fail to complete meiosis and show defects in eggshell formation, mitotic spindle orientation, and cytokinesis. Genetic analysis suggests that the spe-11 gene is expressed before the completion of spermatogenesis and that the wild-type locus encodes a product that is present in sperm and participates, directly or indirectly, in initiating the correct program of early events in C. elegans embryos. Such an ontogenetic role of the spe-11+ gene product in early embryogenesis distinguishes spe-11 mutations from the two paternal-effect mutations identified in Drosophila, ms(3)K81 and pal, which primarily affect chromosome behavior. Analysis of spe-11 provides the first step toward genetic dissection of the functions of the sperm in early embryogenesis in C. elegans.

Animals↗

PubMed1978

Cell culture of individual Drosophila embryos. II. Culture of X-linked embryonic lethals.

Results are reported from the culturing in vitro of cells from individual early gastrulae of the following four groups of X-linked embryonic lethal mutants of Drosophila melanogaster. (1) Notch lethals, Five Notch mutants were studied which have been reported to give similar abnormalities in whole embryos: the nervous system displays a three-fold hypertrophy as part of a shift in the pattern of differentiation within ectodermal derivatives, and mesodermal derivatives do not differentiate. An hypertrophy of nerve was found in cell cultures prepared from embryos of all five mutants. In addition, four of the five alleles consistently gave abnormalities of muscle differentiation: when compared to controls, Notch cultures had a reduced frequency of myotubes, and displayed unusual clusters of myocytes which had either failed to fuse or had fused incompletely. Results from mixed cultures prepared from two embryos were consistent with the autonomous expression of nerve and muscle abnormalities by Notch-8 cells in the presence of wild-type cells. It is argued that the Notch locus has a direct role in the differentiation of both nerve and muscle. (2) white deficiencies. Cells carrying either of two deficiencies gave a clear-cut pattern of abnormalities: initial cellular differentiations were normal, but nerve, muscle and fat-body cells progressively deteriorated during the culture period. Mixed cultures showed that wild-type cells could not 'rescue' mutant muscle and fat-body cells; however, the status of the autonomy of mutant nerve abnormalities in these cultures was unclear. Both white deficiencies remove cytological band 3C1, and this permits a comparison of results with those from cultures of cells from Notch-8 embryos (also deficient for 3C1). Abnormalities displayed in cultures of the two types of mutant show no overlap. Therefore no consistent cellular abnormality can be attributed to absence of band 3C1. (3) lethal(1)myospheroid. In contrast to earlier observations on in vitro cell cultures (Donady & Seecof, 1972) muscle was seen to differentiate, though its morphology was extremely abnormal. Observations indicated that all cell types within the cultures had poor properties of adhesion to a glass substrate. It is argued that the observed abnormalities are not consistent with a mutant lesion which is restricted to the basement membrane (contra Wright, 1960), and that all cell types carry a basic defect which may reside in the cell membrane. (4) shibirets alleles. Cultures of two temperature-sensitive lethal shibire alleles (shits1), shits3) were normal at the permissive temperature of 22 degrees C. At the restrictive temperature (29 degrees C) early cell differentiation was normal but subsequent development was blocked. This blockage could be partially reversed by shifting cultures to the permissive temperature after as much as 10 days exposure to the high temperature. It is suggested that shits cells are mutant in a process which is basic to several cell types.

Animals↗

PubMed2006

Early embryonic lethality due to targeted inactivation of DNA ligase III.

DNA ligases catalyze the joining of strand breaks in the phosphodiester backbone of duplex DNA and play essential roles in DNA replication, recombination, repair, and maintenance of genomic integrity. Three mammalian DNA ligase genes have been identified, and their corresponding ligases play distinct roles in DNA metabolism. DNA ligase III is proposed to be involved in the repairing of DNA single-strand breaks, but its precise role has not yet been demonstrated directly. To determine its role in DNA repair, cellular growth, and embryonic development, we introduced targeted interruption of the DNA ligase III (LIG3) gene into the mouse. Mice homozygous for LIG3 disruption showed early embryonic lethality. We found that the mutant embryonic developmental process stops at 8.5 days postcoitum (dpc), and excessive cell death occurs at 9.5 dpc. LIG3 mutant cells have relatively normal XRCC1 levels but elevated sister chromatid exchange. These findings indicate that DNA ligase III is involved in essential DNA repair activities required for early embryonic development and therefore cannot be replaced by other DNA ligases.

Animals↗

PubMed2004

Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression.

The human embryonic-lethal abnormal vision-like protein HuR is involved in the regulation of mRNA turnover and serves as a shuttling protein between the nucleus and the cytoplasm that stabilizes mRNAs containing adenine- and uridine-rich elements in their 3' untranslated region. We have shown recently that expression of cyclooxygenase (COX)-2 is related to poor prognosis in ovarian carcinoma. Other studies have shown that the COX-2 mRNA contains an adenine- and uridine-rich element and is stabilized by HuR. In this study, we investigated the expression and cellular distribution of HuR in 83 primary ovarian carcinomas, 16 borderline tumors of the ovary, 3 normal ovaries, and 9 ovarian carcinoma cell lines. Expression of HuR was detected in all cell lines on the mRNA and protein level and showed a predominantly nuclear staining in OVCAR-3 cells by confocal microscopy. In an immunohistochemical evaluation of human ovarian carcinomas, HuR showed a nuclear expression in 81% of tumors. In addition, a cytoplasmic expression of HuR was observed in a subgroup of 45% of ovarian carcinomas. Nuclear as well as cytoplasmic expression of HuR was significantly increased in ovarian carcinomas compared with borderline tumors or normal ovaries. In univariate analysis, a significant association between cytoplasmic HuR expression and increased COX-2 expression (P = 0.025) as well as between histological grade (P = 0.008) and mitotic activity (P = 0.002) was observed, although nuclear expression of HuR was not correlated with COX-2 expression or other clinicopathological parameters. In Kaplan-Meier survival analysis, increased cytoplasmic expression of HuR was a significant prognostic indicator for progression-free survival (P = 0.03) as well as overall survival (P = 0.007). In multivariate analysis using the Cox regression model, cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival with a relative risk of 2.62 (95% confidence interval, 1.32-5.19). Our results suggest that there is a dysregulation of cellular distribution of the mRNA stability factor HuR in a subset of invasive ovarian carcinomas. This dysregulation appears to result in an increased expression of COX-2, an increased proliferative rate, and may lead to a reduced survival time. Additional studies are required to analyze the downstream effects of increased cytoplasmic expression of HuR. In addition, it would be interesting to investigate the prognostic role of increased cytoplasmic expression of HuR in prospective studies.

Analysis of Variance↗

PubMed2004

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality.

The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N'-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.

Animals↗

PubMed2003

A gain-of-function mutation in oma-1, a C. elegans gene required for oocyte maturation, results in delayed degradation of maternal proteins and embryonic lethality.

In vertebrates, oocytes undergo maturation, arrest in metaphase II, and can then be fertilized by sperm. Fertilization initiates molecular events that lead to the activation of early embryonic development. In Caenorhabditis elegans, where no delay between oocyte maturation and fertilization is apparent, oocyte maturation and fertilization must be tightly coordinated. It is not clear what coordinates the transition from an oocyte to an embryo in C. elegans, but regulated turnover of oocyte-specific proteins contributes to the process. We describe here a gain-of-function mutation (zu405) in a gene that is essential for oocyte maturation, oma-1. In wild type animals, OMA-1 protein is expressed at a high level exclusively in oocytes and newly fertilized embryos and is degraded rapidly after the first mitotic division. The zu405 mutation results in improper degradation of the OMA-1 protein in embryos. In oma-1(zu405) embryos, the C blastomere is transformed to the EMS blastomere fate, resulting in embryonic lethality. We show that degradation of several maternally supplied cell fate determinants, including SKN-1, PIE-1, MEX-3, and MEX-5, is delayed in oma-1(zu405) mutant embryos. In wild type embryos, SKN-1 functions in EMS for EMS blastomere fate specification. A decreased level of maternal SKN-1 protein in the C blastomere relative to EMS is believed to be responsible for this cell expressing the C, instead of the EMS, fate. Delayed degradation of maternal SKN-1 protein in oma-1(zu405) embryos and resultant elevated levels in C blastomere is likely responsible for the observed C-to-EMS blastomere fate transformation. These observations suggest that oma-1, in addition to its role in oocyte maturation, contributes to early embryonic development by regulating the temporal degradation of maternal proteins in early C. elegans embryos.

Animals↗

PubMed2004

Placental failure and impaired vasculogenesis result in embryonic lethality for neuropathy target esterase-deficient mice.

Age-dependent neurodegeneration resulting from widespread apoptosis of neurons and glia characterize the Drosophila Swiss Cheese (SWS) mutant. Neuropathy target esterase (NTE), the vertebrate homologue of SWS, reacts with organophosphates which initiate a syndrome of axonal degeneration. NTE is expressed in neurons and a variety of nonneuronal cell types in adults and fetal mice. To investigate the physiological functions of NTE, we inactivated its gene by targeted mutagenesis in embryonic stem cells. Heterozygous NTE(+/-) mice displayed a 50% reduction in NTE activity but underwent normal organ development. Complete inactivation of the NTE gene resulted in embryonic lethality, which became evident after gastrulation at embryonic day 9 postcoitum (E9). As early as E7.5, mutant embryos revealed growth retardation which did not reflect impaired cell proliferation but rather resulted from failed placental development; as a consequence, massive apoptosis within the developing embryo preceded its resorption. Histological analysis indicated that NTE is essential for the formation of the labyrinth layer and survival and differentiation of secondary giant cells. Additionally, impairment of vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development.

Alleles↗

PubMed2000

Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice.

Mice with a total deficiency in blood coagulation Factor X (FX) were generated by targeted replacement of an 18-kb fragment of the FX gene, comprising all exons encoding the mature FX protein, with a neo(r) cassette. The genotype distribution among the offspring from heterozygous breeding pairs suggested that FX deficiency resulted in partial embryonic lethality, with approximately one-third of the FX-/- embryos dying around embryonic day (E) 11.5-12.5. Two of 44 non-resorbed FX-/- embryos analyzed at these stages showed signs of massive bleeding, one of which into the brain ventricles, but no histological defects in the vasculature of these embryos or their yolk sac were observed. The remainder of the FX-/- embryos appeared normal and survived to term, but the majority of neonates (90%) died within 5 days, most frequently from intraabdominal bleeding. The remaining FX-/- animals succumbed between postnatal day (P)5 and P20 with intraabdominal, subcutaneous, or intracranial bleeding or a combination thereof. The lethal phenotype of the FX-/- mice illustrates the importance of FX function in embryonic and postnatal survival and demonstrates that these mice serve as effective models of the bleeding disorders observed in severe FX deficiency in humans.

Animals↗

PubMed2004

grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten+/- mice.

PTEN is a tumor suppressor gene implicated in both sporadic cancers and inherited tumor-prone syndromes. Here we show that pten+/- mice display a partially penetrant embryonic lethality. This lethality is associated with defects in both neural and placental development. Notably, this lethality is completely rescued by grb2 haploinsufficiency. In contrast, grb2 heterozygosity did not alter tumorigenesis in either pten+/- or T cell-specific pten-/- mice. grb2-/hypomorph murine embryonic fibroblasts (MEFs) show decreased activation of both PKB and Erk upon stimulation with epidermal growth factor, whereas grb2-/hypomorph; pten+/- MEFs activate PKB but not Erk normally. Similarly, grb2-/hypomorph fibroblasts die in low serum, and this phenotype is rescued by pten haploinsufficiency. Activation of both PKB and Erk as well as survival in low serum-containing media are all rescued by reexpression of Grb2 containing mutations within the N-terminal Src homology 3 (SH3) domain, but not by C-terminal SH3 domain mutants. The N-terminal SH3 domain mutants fail to bind to Sos, whereas the C-terminal SH3 domain mutants fail to bind to Gab1, suggesting that Erk and PKB activation in fibroblasts in response to epidermal growth factor depends on Gab1 or other C-terminal SH3 domain-interacting proteins, but not on Sos. Thus, PTEN/phosphatidylinositol 3' kinase signaling requires Grb2 during both embryonic development and fibroblast survival, but Grb2 heterozygosity does not effect tumorigenesis in pten-deficient mice. In fibroblasts, survival signals emanating from the epidermal growth factor receptor appear to be PKB-dependent, and this activation depends on the C-terminal SH3 domain of Grb2, likely through the interaction of Grb2 with Gab1.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Mutation of the mouse Rad17 gene leads to embryonic lethality and reveals a role in DNA damage-dependent recombination.

Genetic defects in DNA repair mechanisms and cell cycle checkpoint (CCC) genes result in increased genomic instability and cancer predisposition. Discovery of mammalian homologs of yeast CCC genes suggests conservation of checkpoint mechanisms between yeast and mammals. However, the role of many CCC genes in higher eukaryotes remains elusive. Here, we report that targeted deletion of an N-terminal part of mRad17, the mouse homolog of the Schizosaccharomyces pombe Rad17 checkpoint clamp-loader component, resulted in embryonic lethality during early/mid-gestation. In contrast to mouse embryos, embryonic stem (ES) cells, isolated from mRad17(5'Delta/5'Delta) embryos, produced truncated mRad17 and were viable. These cells displayed hypersensitivity to various DNA-damaging agents. Surprisingly, mRad17(5'Delta/5'Delta) ES cells were able to arrest cell cycle progression upon induction of DNA damage. However, they displayed impaired homologous recombination as evidenced by a strongly reduced gene targeting efficiency. In addition to a possible role in DNA damage-induced CCC, based on sequence homology, our results indicate that mRad17 has a function in DNA damage-dependent recombination that may be responsible for the sensitivity to DNA-damaging agents.

Amino Acid Sequence↗

PubMed2000

Mcl-1 deficiency results in peri-implantation embryonic lethality.

We disrupted the Mcl-1 locus in murine ES cells to determine the developmental roles of this Bcl-2 family member. Deletion of Mcl-1 resulted in peri-implantation embryonic lethality. Mcl-1(-/-) embryos do not implant in utero, but could be recovered at E3.5-4.0. Null blastocysts failed to hatch or attach in vitro, indicating a trophectoderm defect, although the inner cell mass could grow in culture. Of note, Mcl-1(-/-) blastocysts showed no evidence of increased apoptosis, but exhibited a delay in maturation beyond the precompaction stage. This model indicates that Mcl-1 is essential for preimplantation development and implantation, and suggests that it has a function beyond regulating apoptosis.

Animals↗

PubMed1996

Targeted disruption of the murine tissue factor gene results in embryonic lethality.

Tissue factor (TF) is an integral membrane glycoprotein that is believed to be the physiologic initiator of the blood coagulation cascade. Disruption of the mouse tissue factor gene leads to embryonic lethality between days E9.5-E11.5 of gestation. On E9.5, TF(-/-) embryos appear indistinguishable from their TF(+/+) and TF(+/-) littermates. By E10.5, TF(-/-) embryos are severely growth retarded, appear nearly bloodless, and are in most cases dead. Initial observations suggest that TF(-/-) embryos are dying of circulatory failure. Approximately 15% of the TF(-/-) embryos survive beyond E10.5, but none complete gestation. Heterozygotes appear normal and free of bleeding complications.

Animals↗

PubMed2001

Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive human disease whose clinical features include growth retardation, immunodeficiency, and increased susceptibility to lymphoid malignancies. Cells from NBS patients exhibit gamma-irradiation sensitivity, S-phase checkpoint defects, and genomic instability. Recently, it was demonstrated that this chromosomal breakage syndrome is caused by mutations in the NBS1 gene that result in a total loss of full-length NBS1 expression. Here we report that in contrast to the viability of NBS patients, targeted inactivation of NBS1 in mice leads to early embryonic lethality in utero and is associated with poorly developed embryonic and extraembryonic tissues. Mutant blastocysts showed greatly diminished expansion of the inner cell mass in culture, and this finding suggests that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Together, our results indicate that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability.

Animals↗

PubMed2002

Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with increased cancer susceptibility. The X-linked form is due to mutations in the DKC1 gene encoding dyskerin, a nucleolar protein predicted to be involved in rRNA processing and associated with the telomerase complex. Available evidence suggests the pathology of DC is due to telomerase defects. We have used the inducible Cre/loxP system to produce deletions in the murine Dkc1 gene in early embryogenesis. A large deletion lacking exons 12-15 and a small deletion lacking only the last exon, were produced. We found both deletions showed a parent-of-origin effect with 100% embryonic lethality when the mutation occurred on the maternal Dkc1. Embryonic analysis at day E7.5 and E9.5 showed no male embryos carrying either deletion whereas females with maternally derived deletions died around day E9.5, with degeneration of the extra embryonic tissue, in which the paternal X-chromosome is inactivated. Female mice carrying the deletion in the paternally derived Dkc1 show extreme skewing of X-inactivation with the wild type X-chromosome active in all cells. Since mice with no telomerase are viable in the first generations the lethality we observe is unlikely to be due to the effects of mutated dyskerin on telomerase activity.

Animals↗

PubMed2000

In vivo immunological function of mast cells derived from embryonic stem cells: an approach for the rapid analysis of even embryonic lethal mutations in adult mice in vivo.

An important goal of tissue engineering is to achieve reconstitution of specific functionally active cell types by transplantation of differentiated cell populations derived from normal or genetically altered embryonic stem cells in vitro. We find that mast cells derived in vitro from wild-type or genetically manipulated embryonic stem cells can survive and orchestrate immunologically specific IgE-dependent reactions after transplantation into mast cell-deficient Kit(W)/Kit(W-v) mice. These findings define a unique approach for analyzing the effects of mutations of any genes that are expressed in mast cells, including embryonic lethal mutations, in vitro or in vivo.

Anaphylaxis↗

PubMed1984

Insertion of retrovirus into the first intron of alpha 1(I) collagen gene to embryonic lethal mutation in mice.

Integration of the Moloney murine leukemia virus (M-MuLV) into the germ line of Mov-13 mice blocked formation of stable alpha 1(I) collagen mRNA and led to an embryonic lethal mutation. A 14-kilobase fragment representing the integration site of the virus was molecularly cloned and identified as the alpha 1(I) collagen gene. Sequence and nuclease S1 mapping analyses were performed to characterize the position of the proviral genome in relation to the transcriptional map of the mutated gene. The results indicated that the virus has inserted into the first intron 19 base pairs downstream of the intron/exon boundary. Sequence comparison showed a striking homology of exon sequences and sequences up to 215 base pairs upstream of the mRNA start between the mouse and the human alpha 1(I) collagen gene. This indicates that the sequences upstream of the mRNA start are highly conserved during evolution, suggesting that this region has an important role in the control of tissue-specific collagen expression.

Amino Acid Sequence↗

PubMed2006

Targeted disruption of the mouse Asna1 gene results in embryonic lethality.

The bacterial ArsA ATPase is the catalytic component of an oxyanion pump that is responsible for resistance to arsenicals and antimonials. Homologues of the bacterial ArsA ATPase are widespread in nature. We had earlier identified the mouse homologue (Asna1) that exhibits 27% identity to the bacterial ArsA ATPase. To identify the physiological role of the protein, heterozygous Asna1 knockout mice (Asna1+/-) were generated by homologous recombination. The Asna1+/- mice displayed similar phenotype as the wild-type mice. However, early embryonic lethality was observed in homozygous Asna1 knockout embryos, between E3.5 (E=embryonic day) and E8.5 stage. These findings indicate that Asna1 plays a crucial role during early embryonic development.

Animals↗

PubMed2003

Aberrant myofibril assembly in tropomodulin1 null mice leads to aborted heart development and embryonic lethality.

Tropomodulin1 (Tmod1) caps thin filament pointed ends in striated muscle, where it controls filament lengths by regulating actin dynamics. Here, we investigated myofibril assembly and heart development in a Tmod1 knockout mouse. In the absence of Tmod1, embryonic development appeared normal up to embryonic day (E) 8.5. By E9.5, heart defects were evident, including aborted development of the myocardium and inability to pump, leading to embryonic lethality by E10.5. Confocal microscopy of hearts of E8-8.5 Tmod1 null embryos revealed structures resembling nascent myofibrils with continuous F-actin staining and periodic dots of alpha-actinin, indicating that I-Z-I complexes assembled in the absence of Tmod1. Myomesin, a thick filament component, was also assembled normally along these structures, indicating that thick filament assembly is independent of Tmod1. However, myofibrils did not become striated, and gaps in F-actin staining (H zones) were never observed. We conclude that Tmod1 is required for regulation of actin filament lengths and myofibril maturation; this is critical for heart morphogenesis during embryonic development.

Actinin↗