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R T Bronson

Publications and source records attributed to R T Bronson.

At least 127 records · Page 7Linked to original sources
PubMed1994

Cooperative tumorigenic effects of germline mutations in Rb and p53.

The tumour suppressor genes Rb and p53 are mutated in several types of human cancer, and many tumour types carry mutations in both genes. To study how these genes normally function, we and others have created mouse strains with Rb and p53 mutations. Here we describe the phenotypic effects of combined germline mutations in these two tumour suppressor genes. Mice mutant for both genes have reduced viability and exhibit novel pathology including pinealoblastomas, islet cell tumours, bronchial epithelial hyperplasia and retinal dysplasia. These data indicate that mutations in Rb and p53 can cooperate in the transformation of certain cell types in the mouse.

Adenoma, Islet Cell↗
PubMed1994

Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency.

A spontaneous autosomal recessive mutation causing disordered morphogenesis of the adrenal cortex has been identified in DW/J inbred strain mice and named adrenocortical dysplasia (acd). The acd mutant gene has been mapped just proximal to oligosyndactyly (Os) and esterase-1 (Es-1) in the central region of chromosome 8. Both male and female acd/acd mice are characterized by reduced survival, retarded growth, skin hyperpigmentation, poorly developed pelage and focal ureteral blockage leading to hydronephrosis. Morphometric measurements showed that acd/acd cortical cells and nuclei were increased sevenfold in volume; nuclei often showed a variety of inclusions. Cortical cells of acd/acd mice contained large numbers of mitochondria, smooth endoplasmic reticulum and lipid droplets characteristic of steroidogenic cells. While cortical X-zones failed to develop in acd/acd adrenals, medullary cells and nuclei were unaffected by mutant gene action. Resting serum corticosterone levels in female, but not male, mutant mice were significantly lower than in +/? normal littermates, whereas ACTH levels were significantly elevated in mutants of both sexes. Serum aldosterone levels were normal in acd/acd mice. Functional studies of adrenals cultured in vitro revealed that acd/acd adrenals secreted reduced amounts of corticosterone per pair of glands under both basal and ACTH-stimulated conditions. However, correction of the corticosterone secretion data to mg cortical mass in culture showed that the mutant cortical tissue secreted the same amount of glucocorticoid as did their +/? normal littermate glands. We conclude that the acd mutant gene acts in an unknown fashion to cause a fundamental defect in cellular proliferation in the adrenal cortex, leading to compensatory marked hypertrophy of cortical cells and grossly enlarged nuclei. The role of acd action in adrenal cortical development remains to be established.

Adrenal Cortex↗
PubMed1994

Retinal degeneration in motor neuron degeneration: a mouse model of ceroid lipofuscinosis.

PURPOSE: To evaluate the retinal degeneration of the motor neuron degeneration (mnd) mouse, and to confirm its inheritance pattern and gene location. METHODS: In screening the mnd/mnd mouse for ocular disease, a retinal degeneration was found that was evaluated by serial electroretinography, histology, electron microscopy, indirect ophthalmoscopy, and genetic and linkage analysis. RESULTS: In homozygous mnd mice, photoreceptor and outer nuclear layers show cell loss by 5 weeks after birth. By 2 months, the peripheral retina is preferentially thinner than central retina, and by 6 months the entire retina is reduced in thickness. The electroretinogram was extinguished by 6 months. Transmission electron microscopy at 3 and 6 months showed distinct cytoplasmic inclusions characteristic of the curvilinear profiles seen in human ceroid lipofuscinosis. Genetic analyses show that the retinal degeneration in mnd mice is inherited as a single autosomal gene with recessive expression, and a three-point cross placed the retinal degeneration at the mnd locus on the proximal end of mouse chromosome 8. Crosses with other known strains with retinal degeneration were normal. CONCLUSIONS. The mnd mouse model is similar to the juvenile onset Spielmeyer-Vogt form of ceroid lipofuscinosis (Batten disease), and provides a good model for the retinal degeneration found in these patients.

Alleles↗
PubMed1993

Prognosis after surgical excision of cerebral meningiomas in cats: 17 cases (1986-1992).

Long-term follow-up information was obtained for 17 cats with cerebral meningiomas treated by surgical excision. Three cats died or were euthanatized in the immediate postoperative period: 2 cats, because of brain herniation and 1 cat, because of acute renal failure. In the remaining 14 cats, most clinical signs resolved within 1 week of surgery. Three cats (21.4%) had confirmed or presumed local tumor recurrence. Two of these cats developed recurrent neurologic signs, and died or were euthanatized at 3 and 9 months, respectively, after surgery. One cat was euthanatized for an unrelated problem 72 months after surgery, and on postmortem examination, had a recurrent meningioma at the surgery site. The remaining 11 cats (78.6%) did not develop evidence of local tumor recurrence within follow-up periods ranging from 18 to 47 months (median, 27 months).

Animals↗
PubMed1993

Age-related gliosis in the white matter of mice.

A histopathologic study of the brains from 96 mice, ranging in age from 3 to 57 months in age, documents an age-associated increase in hypertrophic astrocytes in white matter. This report of gliosis is distinct from previously reported proliferation of glial cells in the grey matter. Four genotypes, CBA/HT6J, C57BL/6J, B6CBAT6F1J, and B6C3F1 were positive for this age-related lesion. Most very old mice utilized in this study were calorically restricted, a dietary manipulation long known to result in increased longevity in rodents. Caloric restriction appears to delay the age associated increase of this lesion. Immunoperoxidase staining for the astrocyte-specific glial fibrillary acidic protein (GFAP) confirmed the progressive increase in the density of stainable astrocytes with increase in age. GFAP staining of white matter increased in both diet groups with age. These findings present an interesting model for the study of aberrant cellular activity and perhaps neurodegeneration, modulated by caloric restriction.

Aging↗
PubMed1993

Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease).

Pathological studies of mice homozygous for the motor neuron degeneration (Mnd) mutation show abnormalities similar to those of the human neuronal ceroid lipofuscinoses: sudanophilic, autofluorescent intraneuronal inclusions that are immunoreactive with antibodies to subunit c of mitochondrial ATP synthase. Ultrastructurally, the inclusions have the pentalaminar structure characteristic of some form of human neuronal ceroid lipofuscinosis and of canine and ovine models of neuronal ceroid lipofuscinosis. Similar inclusions are observed in many somatic organs and in the retina, which develops photoreceptor degeneration. This mutation, previously considered a model of amyotrophic lateral sclerosis, may be a useful model for molecular and genetic studies of human neuronal ceroid lipofuscinosis because mice have been well characterized genetically. Since they are inexpensive to breed and maintain, they can also be used to test therapeutic interventions.

Animals↗
PubMed1993

Pyvs: a dominantly acting gene in C3H/BiDa mice conferring susceptibility to tumor induction by polyoma virus.

Results in a previous report established the presence of dominant genetic factor(s) in C3H/BiDa mice which contributed to the unusually high susceptibility of this strain to polyoma virus-induced tumors (Freund et al. (1992) Virology 191, 724-731). Here we show that C57BR/cdJ mice, while identical to C3H/BiDa at the H-2 locus, are almost completely lacking in susceptibility. Analysis of crosses between these two H-2k strains has shown that susceptibility is due to a single dominant autosomal gene, designated Pyvs. On an H-2k background, Pyvs acts in a highly penetrant manner to confer susceptibility to induction of a broad range of tumors by the virus. Analysis of F1 mice between C3H/BiDa and the highly resistant C57BL/6 (H-2b) strain shows that Pyvs can partially overcome the immunologically mediated resistance associated with an H-2b haplotype. Pyvs does not encode cell receptors for the virus, nor does it affect levels of virus replication or anti-viral humoral responses in the host. Studies with early passage embryo fibroblasts in culture show that Pyvs does not affect intracellular events essential for either productive infection or cell transformation by the virus. Pyvs thus determines a generalized susceptibility of the host to polyoma-induced tumors but apparently does not act at the level of target cells for tumor induction.

3T3 Cells↗
PubMed1993

FRAR course on laboratory approaches to aging. The role of pathology in rodent experimental gerontology.

The distinction between aging and age-related disease is a blurred one at best. Pathologic lesions and diseases, while having obvious importance for the well-being of an individual, are not more indicative of aging than are silent or benign aging changes. All lesions are useful as biomarkers of aging. They are definable, and can be characterized in terms of their prevalence and severity in different species, genotypes, genders, and age groups. Some data from previous studies are presented as examples. Many lesions of aging are quite restricted, in terms of prevalence or severity, to specific genotypes, species or genders. Recognition of the very great diversity of lesion biomarkers between genotypes, genders and species should prevent investigators from extrapolating findings in one genotype-gender to any other.

Aging↗
PubMed1993

Segmental trisomy as a mouse model for Down syndrome.

Mice trisomic for Chromosome (Chr) 16 have been used extensively as an animal model for human Down Syndrome (Trisomy 21). This system has drawbacks, however: trisomy for all of Chr 16 is incompatible with postnatal survival and produces trisomy for many more genes than those conserved in human Chr 21. We report here the development and preliminary characterization of mice that are trisomic for only the segment of mouse Chr 16 that is conserved in human Chr 21. While these segmentally trisomic mice, Ts(17(16)) 65Dn, do not appear to have all the features characteristic of Down Syndrome, they represent a mouse model that survives to adulthood and may be useful to study features of Down Syndrome that develop later in life, such as susceptibility to infection, increased incidence of leukemia, and Alzheimer-like neuropathology.

Animals↗
PubMed1993

Husbandry factors and the prevalence of age-related amyloidosis in mice.

A retrospective study of the prevalence of amyloidosis in mice from several facilities was done. Amyloid deposition is an age-related lesion. The influence of common laboratory factors on the occurrence of this lesion was analyzed. This study documented genotypic difference in susceptibility to amyloidosis and showed that caging and pathogen status both impact on the number of cases of amyloidosis seen in a population. The lowest percentage of affected mice was seen when the animals were individually caged in a specific pathogen-free facility where conditions of stress were minimized.

Age Factors↗
PubMed1992

Effects of an Rb mutation in the mouse.

The retinoblastoma gene is mutated in several types of human cancer and is the best characterized of the tumour-suppressor genes. A mouse strain has been constructed in which one allele of Rb is disrupted. These heterozygous animals are not predisposed to retinoblastoma, but some display pituitary tumours arising from cells in which the wild-type Rb allele is absent. Embryos homozygous for the mutation die between days 14 and 15 of gestation, exhibiting neuronal cell death and defective erythropoiesis.

Amino Acid Sequence↗
PubMed1992

Polyoma virus middle T is essential for virus replication and persistence as well as for tumor induction in mice.

A mutant strain of polyoma virus encoding a truncated middle T protein has been studied for its ability to replicate and induce tumors following inoculation into newborn mice. Virus replication in the acute period prior to expected onset of tumors as well as persistence of virus in older animals were followed. The mutant virus proved to be defective in replication and persistence and failed to induce tumors. These results demonstrated that middle T plays an essential role in productive viral infection in the animal. Since the mutant virus encodes normal large and small T proteins, the results also indicate that functions associated with these T antigens, including large T binding of the retinoblastoma tumor suppressor gene product and the ability to immortalize, are insufficient to cause development of tumors in this system.

Aging↗
PubMed1992

Altered histopathology in protein-deprived mice during Sendai virus pneumonia: evidence for delayed inflammatory response and recovery.

The morphology of the lungs and airway during the course of respiratory infection caused by Sendai virus was examined in normal (20% protein diet) and malnourished (2% protein diet) BALB/c mice. Mortality in normal Sendai-infected mice was 0 compared with 71% in the infected malnourished group. Virus was isolated until day 6 in normally fed mice and until day 9 in the malnourished group. Pulmonary inflammation was largely mononuclear and began in the normally nourished animals on day 3, peaked at day 6, and reverted almost to normal by 30 days. In the malnourished group, inflammation was delayed by about 1 day and fell further behind during the first week. It peaked 10-13 days after infection and was still present with little resolution by day 30. These findings may have relevance to the high mortality of acute respiratory diseases in children of the developing world.

Acute Disease↗
PubMed1992

Genetic and age related models of neurodegeneration in mice: dystrophic axons.

Dystrophic axons (DA) are non-specific lesions that occur in a wide variety of human and animal diseases. In this paper we describe the distribution of these lesions in three newly discovered mouse neurological mutants. The distribution of DA in these mutants is defined by their names, lumbosacral neuroaxonal dystrophy (lnd), located on Chromosome 7, generalized neuroaxonal dystrophy (gnd) and vestibulomotor degeneration (vmd). The last mutant, which has degeneration as well as DA in lateral vestibular nucleus and vestibulo-spinal tracts, dies in the first weeks of life; the first two live for approximately one year. A previously described mutation, dystonia musculorum (dt), was found to produce generalized DA like gnd, but dt/dt mutants die at an early age. DA were also found to occur in the nuclei gracilis and cuneatus, in the area of Clark's column and in lumbo-sacral spinal cord in aging normal mice either fed ad libitum or at a level of 40% dietary restriction. The dietary regimen had little effect on the numbers of DA observed in susceptible areas of the neuroaxis. The mutant models of neuroaxonal dystrophy may prove useful in studies of the pathophysiology of DA in general and of specific inherited diseases of man, such as infantile neuroaxonal dystrophy and Hallervordin-Spatz disease.

Aging↗
PubMed1992

Separation of immortalization from tumor induction with polyoma large T mutants that fail to bind the retinoblastoma gene product.

The mouse polyomavirus encodes a tumor-suppressor gene inactivator in its large T protein and a proto-oncogene activator in its middle T protein. We have used site-directed mutagenesis to selectively inactivate the former function without affecting the latter. Two mutant viruses were constructed to encode altered large T proteins that fail to bind the retinoblastoma tumor-suppressor gene product pRB, along with normal small and middle T proteins. The pRB-binding mutants proved to be defective in immortalization of primary rat embryo fibroblasts by a variety of tests. Yet they proved capable of transforming both primary and established fibroblasts in culture. Most importantly, the inability of these mutants to bind pRB had little effect on their ability to induce tumors in mice. We conclude that induction of multiple tumor types in this system does not depend on large T-pRB interactions but rather on middle T-dependent pathways. In addition, the ability of this virus to immortalize cells in culture is not essential to its ability to induce tumors in the animal.

Animals↗
PubMed1991

Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.

The c-abl proto-oncogene, which encodes a cytoplasmic protein-tyrosine kinase, is expressed throughout murine gestation and ubiquitously in adult mouse tissues. However, its levels are highest in thymus, spleen, and testes. To examine the in vivo role of c-abl, the gene was disrupted in embryonic stem cells, and the resulting genetically modified cells were used to establish a mouse strain carrying the mutation. Most mice homozygous for the c-abl mutation became runted and died 1 to 2 weeks after birth. In addition, many showed thymic and splenic atrophy and a T and B cell lymphopenia.

Animals↗
PubMed1991

Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation.

In a previous report (Langner, C. A., Birkenmeier, E. H., Ben-Zeev, O., Schotz, M. C., Sweet, H. O., Davisson, M. T., and Gordon, J. I. (1989) J. Biol. Chem. 264, 7994-8003), we characterized the early developmental phenotype of mice that were homozygous for the autosomal recessive fatty liver dystrophy (fld) mutation. Shortly after birth, these mice can be distinguished from their +/? littermates by large pale livers, hypertriglyceridemia, elevations in hepatic apolipoprotein A-IV and apoC-II mRNA levels, and tissue-specific decreases in lipoprotein lipase and hepatic lipase activities. These traits resolve by the early weaning period. We have now characterized a second feature of this mutation: a peripheral neuropathy that becomes manifest by an abnormal gait at the end of the second postnatal week and persists through adulthood. Electron microscopic studies of sciatic nerves from 4-day-to 1-year-old fld/fld mice demonstrated a variety of abnormalities including thin, poorly compacted myelin sheaths, active myelin breakdown, and enlarged Schwann cell mitochondria and nuclei. Western blot analysis of sciatic nerve homogenates prepared from 1 to 3-month-old fld/fld mice and their +/? littermates indicated that homozygous animals have striking reductions in two peripheral nerve myelin-associated proteins, P0 and P2. The steady-state level of apoE, a protein induced during nerve regeneration, is markedly elevated. Furthermore, two axon-specific proteins, neurofilament 68K and growth-associated 43 protein, display altered expression in adult fld/fld sciatic nerves. High performance thin-layer chromatography revealed deficiencies in phospholipids, glycosphingolipids, and some neutral lipids in fld/fld sciatic nerves harvested during the first several months of life (compared to their +/? littermates). Cholesterol esters were elevated in homozygotes. By contrast, no differences in brain lipids were noted between fld/fld animals and their +/? littermates. These data suggest that the fld mutation is associated with an abnormality of myelin formation (dysmyelination) as well as demyelination and axonal degeneration that persists despite apparent resolution of the neonatal hypertriglyceridemia and associated lipase abnormalities. These findings establish the fld/fld mouse as an excellent model system for analyzing homeostatic mechanisms that modulate lipid metabolism in newborn mice and for examining the pathogenesis of peripheral neuropathies associated with dyslipidemias.

Aging↗