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Results for “embryonic lethality”

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PubMed2002

Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia.

The AML1/CBFbeta transcription factor complex, a frequent target of chromosomal translocations in leukemia, is essential for the generation of definitive hematopoietic stem cells. Paradoxically, expression of the acute myeloid leukemia-associated AML1-ETO fusion protein in mice results not in leukemia, but in embryonic lethality due to an absence of normal hematopoiesis. To bypass the embryonic lethality, we generated a mouse strain with a conditional AML1-ETO knockin allele that contains a loxP bracketed transcriptional stop cassette 5' to the AML1-ETO fusion site. Activation of this allele in vivo by Cre-mediated recombination resulted in an enhanced replating efficiency of myeloid progenitors, but it did not block their differentiation, nor was it sufficient to induce leukemia. However, induction of cooperating mutations resulted in the development of an acute myeloid disease that mimicked many of the features of human AML1-ETO-expressing leukemia.

Acute Disease↗

PubMed2004

Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice.

Mdm2 and its homolog Mdm4 inhibit the function of the tumor suppressor p53. Targeted disruption of either mdm2 or mdm4 genes in mice results in embryonic lethality that is completely rescued by concomitant deletion of p53, suggesting that deletion of negative regulators of p53 results in a constitutively active p53. Thus, these mouse models offer a unique in vivo system to assay the functional significance of different p53 modifications. Phosphorylation of serine 389 in murine p53 occurs specifically after ultraviolet-light-induced DNA damage, and phosphorylation of this site enhances p53 activity both in vitro and in vivo. Recently, mice with a serine to alanine substitution at serine 389 (p53S389A) in the endogenous p53 locus were generated. To examine the in vivo significance of serine 389 phosphorylation during embryogenesis, we crossed these mutant mice to mice lacking mdm2 or mdm4. The p53S389A allele did not alter the embryonic lethality of mdm2 or mdm4. Additional crosses to assay the effect of one p53S389A allele with a p53 null allele also did not rescue the lethal phenotypes. In conclusion, the phenotypes due to loss of mdm2 or mdm4 were not even partially rescued by p53S389A, suggesting that p53S389A is functionally wild type during embryogenesis.

Animals↗

PubMed1993

Cytogenetical localization of Zygotic hybrid rescue (Zhr), a Drosophila melanogaster gene that rescues interspecific hybrids from embryonic lethality.

Hybrid females from crosses between Drsophila melanogaster males and females of its sibling species, D. simulans, D. mauritiana, or D. sechellia die as embryos. This lethality is believed to be caused by incompatibility between the X chromosome of D. melanogaster and the maternal cytoplasm. Zygotic hybrid rescue (Zhr) prevents this embryonic lethality and has been cytogenetically mapped to a proximal region of the X chromosome of D. melanogaster, probably in the centromeric heterochromatin. We have carried out high resolution cytological mapping of Zhr using deficiencies and duplications of the X heterochromatin. Deletions of the Zhr+ gene from the hybrid genome exhibit the Zhr phenotype. On the contrary, addition of the wild-type gene to the hybrid genome causes embryonic lethality, regardless of sex. The Zhr locus has been narrowed down to the region covered by Dp(1;f)1162 but not covered Dp(1;f)1205, a chromosome carrying a duplication of heterochromatin located slightly distal to the In(1)sc8 heterochromatic break-point.

Animals↗

PubMed2006

Expression of a modified H19 RNA does not cause embryonic lethality in mice.

The imprinted H19 gene produces a noncoding RNA of unknown function. Targeted and transgenic mouse mutations have shown that this RNA can be deleted and overexpressed without adverse effect. Yet one mutation of the H19 gene displayed an embryonic lethal phenotype in the mouse--the expression of an RNA modified by a short insertion near the 5' end of the transcript (H19(Xba) allele). Expression of this RNA in transgenic mice conferred lethality at day 14 of development. The potential for this mutant to elucidate the function of the H19 RNA supported further investigation of the H19(Xba) phenotype. Since all H19(Xba) transgenic founders died as embryos, an experiment was designed to generate H19(Xba)-expressing mice that could be maintained as an established line. This strategy took advantage of the maternal-specific expression of H19, passing an H19(Xba) knockin allele silently through males and transferring it to females only to generate animals for study. Surprisingly, H19(Xba) knockin mice are fully viable, whether the H19(Xba) allele is inherited paternally or maternally. Experiments to reproduce the original transgene-based lethality were also performed and yielded live-born transgene-expressing animals. These data demonstrate that, contrary to published reports, expression of the H19(Xba) RNA does not cause embryonic lethality in mice.

Animals↗

PubMed2000

Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system.

Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin. We recently showed that Gata3-directed lacZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Gata3 expression, except in thymus and the sympathoadrenal system. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants. We find here that null mutation of Gata3 leads to reduced accumulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine beta-hydroxylase, Dbh) mRNA, whereas several other SNS genes are unaffected. We show that Th and Dbh deficiencies lead to reduced noradrenaline in the SNS, and that noradrenaline deficiency is a proximal cause of death in mutants by feeding catechol intermediates to pregnant dams, thereby partially averting Gata3 mutation-induced lethality. These older, pharmacologically rescued mutants revealed abnormalities that previously could not be detected in untreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cells. Thus we have shown that Gata3 has a role in the differentiation of multiple cell lineages during embryogenesis.

Animals↗

PubMed1999

A system to efficiently maintain embryonic lethal mutations in the flour beetle Tribolium castaneum.

Due to its small size, short life cycle, and easy maintenance, the flour beetle Tribolium castaneum is well suited for the genetic analysis of development. One drawback of Tribolium as a genetic system is, however, the difficulty of keeping embryonic lethal lines. Presently, only few lethal mutations can be kept as balanced stocks. Therefore, heterozygous carriers must be identified anew in every generation in order to maintain a recessive embryonic mutation. To alleviate this problem we have devised a block system that allows the simultaneous processing of many mutant lines or test crosses for visual inspection of larval cuticle phenotypes. Using this technique, one person can maintain about 100 embryonic lethal stocks, which makes feasible the thorough genetic analysis of embryogenesis in this species.

Animals↗

PubMed2002

Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous delta11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated.

Animals↗

PubMed1998

Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abeta1-42/43 expression.

Mutations in presenilin 1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster production of Abeta1-42/43 in FAD patients and transgenic mice. PS1 null mice are embryonic lethal and exhibit axial skeleton malformation and CNS defects. We show that transgenic mouse lines expressing either the wild-type human PS1 protein or human PS1 with the A246E FAD mutation can rescue the PS1 knockout mouse from embryonic lethality to similar degrees, indicating that the mutation does not lead to loss of PS1 function during development. Furthermore, a 50% reduction of PS1 activity in PS1(+/-) mice does not lead to Abeta1-42/43 increase, whereas expression of human mutant PS1 on murine PS1 null background is sufficient to elevate Abeta1-42/43, supporting a gain-of-function activity as the result of the PS1 mutation.

Alzheimer Disease↗

PubMed2003

Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress.

Nrf1 and Nrf2 are members of the CNC family of bZIP transcription factors that exhibit structural similarities, and they are co-expressed in a wide range of tissues during development. Nrf2 has been shown to be dispensable for growth and development in mice. Nrf2-deficient mice, however, are impaired in oxidative stress defense. We previously showed that loss of Nrf1 function in mice results late gestational embryonic lethality. To determine whether Nrf1 and Nrf2 have overlapping functions during early development and in the oxidative stress response, we generated mice that are deficient in both Nrf1 and Nrf2. In contrast to the late embryonic lethality in Nrf1 mutants, compound Nrf1, Nrf2 mutants die early between embryonic days 9 and 10 and exhibit extensive apoptosis that is not observed in the single mutants. Loss of Nrf1 and Nrf2 leads to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death that is reversed by culturing under reduced oxygen tension or the addition of antioxidants. Compound mutant cells also show increased levels of p53 and induction of Noxa, a death effector p53 target gene, suggesting that cell death is potentially mediated by reactive oxygen species activation of p53. Moreover, we show that expression of genes related to antioxidant defense is severely impaired in compound mutant cells compared with single mutant cells. Together, these findings indicate that the functions of Nrf1 and Nrf2 overlap during early development and to a large extent in regulating antioxidant gene expression in cells.

Animals↗

PubMed1993

The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein.

Lethal yellow (Ay) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, Ay expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The Ay mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the Ay mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the Ay mutation disrupts the structure and expression of the Raly gene. The data suggest that the Ay mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with Ay may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.

Agouti Signaling Protein↗

PubMed2002

Deletion of the cancer-amplified coactivator AIB3 results in defective placentation and embryonic lethality.

The amplified in breast cancer-3 (AIB3, ASC-2, RAP250, PRIP, TRBP, NRC, or NcoA6) gene is characterized as a cancer-amplified transcriptional coactivator for nuclear receptors, which include the peroxisome proliferator-activated receptor gamma (PPARgamma). To assess its biological function, we deleted the AIB3 gene in mice by homologous recombination. AIB3(+/-) mice are developmentally normal and fertile. AIB3(-/-) embryos exhibit growth restriction and lethality during 9.75-11.5 days postconception. The embryonic lethality is probably attributed to defects in the development of the placental vascular network and cardiac hypoplasia. These defects include the failure of labyrinthine development, the dilation of maternal blood sinuses, the massive erythrophagocytosis by trophoblasts, the alteration of trophoblast populations, and the lower proliferation of myocardium, which are similar to those encountered in mice lacking PPARgamma or the PPARgamma-binding protein (PBP, TRAP220, or DRIP205). In addition, the transcriptional activities of PPARgamma are significantly affected in mouse embryonic fibroblasts lacking AIB3. These results suggest that AIB3 is required for PPARgamma function in placental development and for normal heart development. These results also indicate that the biological function of AIB3 is not redundant with other classes of nuclear receptor coactivators such as PBP and members of the steroid receptor coactivator family.

Animals↗

PubMed2005

Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects.

Most of the phosphatidylethanolamine (PE) in mammalian cells is synthesized by two pathways, the CDP-ethanolamine pathway and the phosphatidylserine (PS) decarboxylation pathway, the final steps of which operate at spatially distinct sites, the endoplasmic reticulum and mitochondria, respectively. We investigated the importance of the mitochondrial pathway for PE synthesis in mice by generating mice lacking PS decarboxylase activity. Disruption of Pisd in mice resulted in lethality between days 8 and 10 of embryonic development. Electron microscopy of Pisd-/- embryos revealed large numbers of aberrantly shaped mitochondria. In addition, fluorescence confocal microscopy of Pisd-/- embryonic fibroblasts showed fragmented mitochondria. PS decarboxylase activity and mRNA levels in Pisd+/- tissues were approximately one-half of those in wild-type mice. However, heterozygous mice appeared normal, exhibited normal vitality, and the phospholipid composition of livers, testes, brains, and of mitochondria isolated from livers, was the same as in wild-type littermates. The amount and activity of a key enzyme of the CDP-ethanolamine pathway for PE synthesis, CTP:phosphoethanolamine cytidylyltransferase, were increased by 35-40 and 100%, respectively, in tissues of Pisd+/- mice, as judged by immunoblotting; PE synthesis from [3H]ethanolamine was correspondingly increased in hepatocytes. We conclude that the CDP-ethanolamine pathway in mice cannot substitute for a lack of PS decarboxylase during development. Moreover, elimination of PE production in mitochondria causes fragmented, misshapen mitochondria, an abnormality that likely contributes to the embryonic lethality.

Animals↗

PubMed2003

Distortion of the three-dimensional structure of the vnd/NK-2 homeodomain bound to DNA induced by an embryonically lethal A35T point mutation.

The three-dimensional solution structure obtained by NMR of the A35T mutant vnd/NK-2 homeodomain bound to the vnd/NK-2 consensus 16 bp DNA sequence was determined. This mutation to threonine from alanine in position 35 in helix II of the vnd/NK-2 homeodomain is associated with early embryonic lethality in Drosophila melanogaster. Although the unbound mutant protein is not structured, in the DNA-bound state it adopts the three-helix fold characteristic of all known homeodomains, but with alterations relative to the structure of the wild-type analogue. These structural modifications occur, and are accompanied by a 50-fold reduction in the DNA binding affinity, even though most of the protein-DNA interactions originally seen for the wild-type homeodomain are found likewise in the threonine analogue. Alterations include torsional angle changes in the loop between helix I and helix II, and in the turn between helix II and helix III, as well as in a distortion of the usual antiparallel orientation of helix I with respect to helix II. The alteration of the position of leucine 40 in the A35T mutant is proposed to explain the observed 1.27 ppm upfield shift of the corresponding amide proton resonance relative to the value observed for the wild-type analogue. A detailed comparison of the structures of the mutant A35T and wild-type vnd/NK-2 homeodomains bound to the cognate DNA is presented. The consequences of the structural alteration of the DNA-bound A35T mutant vnd/NK-2 protein may constitute the basis of the observed early embryonic lethality.

Animals↗

PubMed1994

Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice.

We have used a retroviral gene trap in embryonic stem (ES) cells to derive a recessive embryonic lethal mouse strain, ROSA beta-geo5. Mutant embryos display an enlarged pericardial cavity, bradycardia, a dilated fourth ventricle in the brain, and die between embryonic days 11 and 12. Whereas heart development in the mutant embryos is extensive, the ventricular wall is abnormally thin with a reduced number of trabeculae. Cloning of the trapped gene indicates that proviral insertion creates a null mutation in the transcriptional enhancer factor 1 (TEF-1) gene. Although transcription of a number of muscle-specific genes believed to be TEF-1 targets appears normal, the defect in cardiogenesis is likely attributable to diminished transcription of one or several cardiac-specific genes.

Amino Acid Sequence↗

PubMed2005

Embryonic lethality in Dear gene-deficient mice: new player in angiogenesis.

The dual endothelin-1/angiotensin II receptor (Dear) binds endothelin-1 (ET-1) and angiotensin II (ANG II) with equal affinities in the Dahl S/JRHS rat strain. To elucidate its physiological significance within the context of multiple receptor isoforms and diverse ET-1 and ANG II functions spanning blood pressure regulation, tumor proliferation, and angiogenesis, we characterized mouse Dear and Dear-deficient mice. Unlike null mutant models of ET-1, ANG II, and all other ET-1 and ANG II receptors, Dear(-/-) deficiency results in impaired angiogenesis, dysregulated neuroepithelial development, and embryonic lethality by embryonic day 12.5. Interestingly, mouse Dear does not bind ANG II, similar to Dahl R/JRHS rat Dear, but binds ET-1 and vascular endothelial growth factor (VEGF) signal peptide (VEGFsp) with equal affinities, suggesting a putative novel multifunction for VEGFsp and a parsimonious mechanism for coordination of VEGF-induced and Dear-mediated pathways. Consistent with its developmental angiogenic role, Dear inhibition results in decreased tumor growth in B16-F10 melanoma cell-induced subcutaneous tumor in female Dear(+/-)/C57BL6BC10 mice, but not in males (age 3.5 mo), and in 127Cs radiation-induced orthotopic mammary tumors in Sprague-Dawley female rats (age range 3-6.5 mo). Altogether, the data identify Dear as a new player in angiogenesis during development downstream to, and nonredundant with, VEGF-mediated pathways, as well as a putative modulator of tumor angiogenesis acting within a gender-specific paradigm.

Animals↗

PubMed2006

Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene.

We recently reported that a germline insertion of a single nucleotide in the rat homologue of the human Birt-Hogg-Dubé gene (BHD) gives rise to dominantly inherited cancer in the Nihon rat model. In this study, we constructed transgenic Nihon rats with introduction of a wild-type Bhd gene to ascertain whether suppression of the Nihon phenotype is possible. Rescue from embryonic lethality of mutant homozygotes (Nihon/Nihon) and suppression of renal carcinogenesis in heterozygotes (Nihon/+) were both observed, defining the germline Bhd mutation in the Nihon rat as an embryonal lethal and tumor predisposing mutation. This transgenic rescue system will be useful to analyse Bhd gene function, its relation to tumorigenesis in vivo, and genetic-environmental interactions in carcinogenesis.

Animals↗

PubMed1995

apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes.

Alleles↗

PubMed2003

Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality.

Fatty acid transport protein-4 (FATP4) is the major FATP in the small intestine. We previously demonstrated, using in vitro antisense experiments, that FATP4 is required for fatty acid uptake into intestinal epithelial cells. To further examine the physiological role of FATP4, mice carrying a targeted deletion of FATP4 were generated. Deletion of one allele of FATP4 resulted in 48% reduction of FATP4 protein levels and a 40% reduction of fatty acid uptake by isolated enterocytes. However, loss of one FATP4 allele did not cause any detectable effects on fat absorption on either a normal or a high fat diet. Deletion of both FATP4 alleles resulted in embryonic lethality as crosses between heterozygous FATP4 parents resulted in no homozygous offspring; furthermore, no homozygous embryos were detected as early as day 9.5 of gestation. Early embryonic lethality has been observed with deletion of other genes involved in lipid absorption in the small intestine, namely microsomal triglyceride transfer protein and apolipoprotein B, and has been attributed to a requirement for fat absorption early in embryonic development across the visceral endoderm. In mice, the extraembryonic endoderm supplies nutrients to the embryo prior to development of a chorioallantoic placenta. In wild-type mice we found that FATP4 protein is highly expressed by the epithelial cells of the visceral endoderm and localized to the brush-border membrane of extraembryonic endodermal cells. This localization is consistent with a role for FATP4 in fat absorption in early embryogenesis and suggests a novel requirement for FATP4 function during development.

Animals↗