Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.

c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply.

Analysis of Pax6 contiguous gene deletions in the mouse, Mus musculus, identifies regions distinct from Pax6 responsible for extreme small-eye and belly-spotting phenotypes.

In the mouse Pax6 function is critical in a dose-dependent manner for proper eye development. Pax6 contiguous gene deletions were shown to be homozygous lethal at an early embryonic stage. Heterozygotes express belly spotting and extreme microphthalmia.

Triosephosphate isomerase activity-deficient mice show haemolytic anaemia in homozygous condition.

A triosephosphate isomerase (TPI) mutant, Tpi1(a-m6Neu), with approximately 57% residual enzyme activity in blood compared with wild-type was detected among offspring of triethylenemelamine-treated male mice. Homozygous mutants with about 13% residual enzyme activity were recovered in progeny of inter se matings of heterozygotes. The loss of TPI activity was evident both in blood and in other tissue extracts.

Relationship of Pax6 activity levels to the extent of eye development in the mouse, Mus musculus.

In this study we extend the mouse Pax6 mutant allelic series to include a homozygous and hemizygous viable hypomorph allele. The Pax6(132-14Neu) allele is a Phe272Ile missense mutation within the third helix of the homeodomain. The mutant Pax6 homeodomain shows greatly reduced binding activity to the P3 DNA binding target.

Genetic, biochemical, and molecular characterization of nine glyceraldehyde-3-phosphate dehydrogenase mutants with reduced enzyme activity in Mus musculus.

The first mutations causing hereditary glyceraldehyde-3-phosphate dehydrogenase (GAPDH) deficiency in the mouse are described. In the course of various mutagenicity experiments with chemical mutagens and irradiation, nine independent mutations causing approximately 50-55% residual activity in blood compared to wild type were identified at the Gapdh structural locus on chromosome 6. Breeding experiments displayed an autosomal semidominant mode of inheritance for all mutants.

Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles.

The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [alpha1(IV)]2[alpha2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages.

Three novel Pax6 alleles in the mouse leading to the same small-eye phenotype caused by different consequences at target promoters.

Purpose: To characterize three new mouse small-eye mutants detected during ethylnitrosourea mutagenesis programs.

Methods: Three new mouse small-eye mutants were morphologically characterized, particularly by in situ hybridization. The mutations were mapped, and the candidate gene was sequenced.

An ENU-induced mutation in Rs1h causes disruption of retinal structure and function.

Purpose: The 44TNJ mutant mouse was generated by the Tennessee Mouse Genome Consortium (TMGC) using an ENU-based mutagenesis screen to produce recessive mutations that affect the eye and brain. Herein we present its retinal phenotype and genetic basis.

Methods: Fourth generation offspring (G4) and confirmed mutants were examined using slit lamp biomicroscopy, funduscopy, histology, immunohistochemistry, and electroretinography (ERG).

Electroretinography as a screening method for mutations causing retinal dysfunction in mice.

Purpose: To detect mice with hereditary retinal impairment, a high-throughput electroretinography (ERG) screening system was established.

Method: Mice from eight different strains without known retinal disorders (102, 129/SvJ, AKR, C57BL/6J, C57BL/6JIco, CBA/CaJ, and DBA/2NCrlBR) and one control strain with retinal degeneration (C3HeB/FeJ) were fixed on a specially constructed sled, ERG electrodes were placed on the cornea, and mice were moved into a Ganzfeld stimulator. From a luminance range of 0.

Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice.

Mutator phenotypes, a common and largely unexplained attribute of human cancer, might be better understood in mouse tumors containing reporter genes for accurate mutation enumeration and analysis. Previous work on peritoneal plasmacytomas (PCTs) in mice suggested that PCTs have a mutator phenotype caused by Myc-deregulating chromosomal translocations and/or phagocyte-induced mutagenesis due to chronic inflammation. To investigate this hypothesis, we generated PCTs that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the assessment of mutations in vivo.

Mutation in intron 6 of the hamster Mitf gene leads to skipping of the subsequent exon and creates a novel animal model for the human Waardenburg syndrome type II.

In the course of analysis of ENU-induced mutations in Syrian hamsters, a novel dominant anophthalmic white mutant (Wh(V203)) with hearing loss was recovered. Because of this phenotype and a close linkage to the Tpi gene, the Mitf gene was considered as a candidate gene. In the Mitf cDNA, a deletion of 76 bp covering the entire exon 7 was detected.

Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdx(a) encoding glucose 6-phosphate dehydrogenase.

Mice harboring the activity-attenuated Gpdx(a-m2Neu) allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.

Moderate G6PD deficiency increases mutation rates in the brain of mice.

Mice that harbored the x-ray-induced low efficiency allele of the major X-linked isozyme of glucose-6-phospate dehydrogenase (G6PD), Gpdx(a-m2Neu), and, in addition, harbored the transgenic shuttle vector for the determination of mutagenesis in vivo, pUR288, were employed to further our understanding of the interdependence of general metabolism, oxidative stress control, and somatic mutagenesis. The Gpdx(a-m2Neu) mutation conferred moderate G6PD deficiency in hemizygous males (Gpdx(a-m2Neu/y)) displaying residual enzyme activities of 27% in red blood cells and 13% in brain (compared to wild-type controls, Gpdx(a/y) males). In spite of this mild phenotype, the brains of G6PD-deficient males exhibited a significant distortion of redox control ( approximately 3-fold decrease in the ratio of reduced glutathione to oxidized glutathione), a considerable accumulation of promutagenic etheno DNA adducts ( approximately 13-fold increase in ethenodeoxyadenosine and approximately 5-fold increase in ethenodeoxycytidine), and a substantial elevation of somatic mutation rates ( approximately 3-fold increase in mutant frequencies in lacZ, the target and reporter gene of mutagenesis in the shuttle vector, pUR288).