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Biomedical subjects

W G Beamer

Publications and source records attributed to W G Beamer.

At least 91 records · Page 5Linked to original sources
PubMed1990

A murine model of mucopolysaccharidosis VII. Gross and microscopic findings in beta-glucuronidase-deficient mice.

This report describes the clinical and pathologic alterations found in mice that have a recessively inherited, essentially complete deficiency of the lysosomal enzyme beta-glucuronidase. Affected animals have a shortened life span and are dysmorphic and dwarfed. Abnormal gait and decreased joint mobility correlate with glycosaminoglycan accumulation in articular tissue and cartilaginous and bony lesions result in extensive skeletal deformation. In these enzyme-deficient animals, lysosomes, distended by fine fibrillar and granular storage material, are particularly prominent in the macrophage system but also occur in other tissues including the skeletal and central nervous systems. The clinical and pathologic abnormalities in these mutant mice closely parallel those identified in humans with mucopolysaccharidoses (MPS). Therefore, these mice provide a well-defined genetic system for the analysis of the pathophysiology of mucopolysaccharidosis type VII, which has many features in common with the other MPS. The mutant mice provide an attractive animal model to test potential therapies for lysosomal storage disease.

Animals↗
PubMed1989

Epidermal growth factor receptors in spontaneous ovarian granulosa cell tumors of SWR-derived mice.

Epidermal growth factor (EGF) receptor binding properties were examined in spontaneous ovarian granulosa cell (GC) tumors from SWR and SWR-derived strains of mice. EGF binding was measured at room temperature in tissue homogenates from GC tumors and normal ovaries from adult randomly cycling mice. GC tumor tissue displayed significantly increased EGF binding and 2 receptor populations (R1 and R2). Normal ovarian tissue appeared to have only one receptor population with a dissociation constant (KD) similar to the R1 (high-affinity) receptor in GC tumors. In subsequent experiments, GC tumor and normal granulosa cells from immature mice were analyzed in primary cultures for EGF binding, immunofluorescence microscopy for receptors, and cell proliferation. After 24 hr in culture, the GC tumors bound 10-fold more EGF/micrograms protein than did normal granulosa cells. GC tumor cells, but not normal granulosa cells, showed specific immunofluorescence when reacted with a polyclonal antibody to mouse EGFR. During 96 hr in culture, GC tumor cells, but not normal cells, showed a significant proliferative response to EGF. In conclusion, the EGF binding capacity is markedly increased in GC tumor cells and the proliferation data suggest that this growth factor supports tumor growth in the SWR model system.

Animals↗
PubMed1989

Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency.

We have characterized a new mutant mouse that has virtually no beta-glucuronidase activity. This biochemical defect causes a murine lysosomal storage disease that has many interesting similarities to human mucopolysaccharidosis type VII (MPS VII; Sly syndrome; beta-glucuronidase deficiency). Genetic analysis showed that the mutation is inherited as an autosomal recessive that maps to the beta-glucuronidase gene complex, [Gus], on the distal end of chromosome 5. Although there is a greater than 200-fold reduction in the beta-glucuronidase mRNA concentration in mutant tissues, Southern blot analysis failed to detect any abnormalities in the structural gene, Gus-sb, or in 17 kb of 5' flanking and 4 kb of 3' flanking sequences. Surprisingly, a sensitive S1 nuclease assay indicated that the relative level of kidney gusmps mRNA responded normally to androgen induction by increasing approximately 11-fold. Analysis of this mutant mouse may offer valuable information on the pathogenesis of human MPS VII and provide a useful system in which to study bone marrow transplantation and gene transfer methods of therapy.

Alleles↗
PubMed1989

Abnormal properties of thyroglobulin in mice with inherited congenital goiter (cog/cog).

A recessive autosomal mutation (cog) in mice that results in congenital goiter was recently described. Since the mutation has been linked to the thyroglobulin (TG) gene, we have studied the immunological and physical properties of TG in cog/cog mice. +/Cog mice, which are phenotypically normal, were used as controls. In a mouse TG RIA the displacement curve produced by cog/cog thyroid extract was not parallel to normal murine TG, and at maximum displacement 15.4% of the tracer was still bound to the antibody. Extract from +/cog thyroid tissue produced parallel and complete displacement. Sucrose density gradient velocity centrifugation followed by RIA was used to determine the sedimentation properties of cog/cog TG. An abnormal pattern was obtained; a small peak in the 3-8S area and a broad, poorly defined peak at 12S and extending to above 27S were present. By comparison, +/cog thyroids had sharp peaks at 19S and 27S. These findings suggest that normal TG contains some immunological determinants that are absent, and some that are altered, in cog/cog TG. They also indicate that the association of 12S subunits to form 19S TG in cog/cog mice is weak and abnormal. Thyroid tissue was labeled with Na125I in vivo and with [35S] methionine in vitro. In cog/cog mice iodine was incorporated predominantly into albumin and other non-TG proteins. However, by polyacrylamide gradient gel electrophoresis, distinct 125I-labeled bands comigrating with normal TG were present. The bands migrating with TG were also precipitable with anti-TG antiserum. In +/cog mice TG was the predominant iodinated molecule. With [35S]methionine labeling, cog/cog and +/cog thyroids formed TG with the same electrophoretic mobilities. These data indicate the cog/cog thyroids synthesize TG of normal, or very nearly normal, size. The immunological and sedimentation properties of this TG are abnormal, supporting the possibility that the cog mutation is in the TG gene.

Animals↗
PubMed1988

Gene for ovarian granulosa cell tumor susceptibility, Gct, in SWXJ recombinant inbred strains of mice revealed by dehydroepiandrosterone.

Spontaneous, malignant ovarian granulosa cell (GC) tumors occur in pubertal SWR and specific SWXJ recombinant inbred strains of mice. Treatment of these mice with dehydroepiandrosterone (DHEA), an adrenal secretory steroid with anticancer actions against spontaneous and carcinogen-induced tumors of different tissues, gave unexpected results. Diet supplemented with 0.4% DHEA (a) induced significantly more GC tumors in spontaneous tumor-susceptible strains (SWR and SWXJ-1, -4, and -9), (b) induced the first GC tumors observed in five previously tumor-free strains (SWXJ-6, -7, -8, -10, and -12), and (c) failed to induce GC tumors in SJL and in the remaining six SWXJ strains (SWXJ-2, -3, -5, -11, -13, and -14). The strain distribution pattern of DHEA-induced GC tumor susceptibility versus resistance was compared with strain distribution patterns for 35 different loci known to distinguish SWR and SJL progenitor strains. A complete match of DHEA-induced GC tumors with pancreas-2 (Pan-2) on mouse chromosome 4 was found. We have named this new locus GC tumor susceptibility (Gct), with the Gcts (susceptible) allele found in SWR and the Gctr (resistant) allele found in SJL mice. The Gct locus is closely linked to pancreas-2, Pan-2, but the order of genes is not yet confirmed. In addition, data from F1 progeny of matings between SWR and selected inbred strains provide suggestive evidence for a second gene controlling GC tumor incidence that we hypothesize involves steroid metabolism. Differences in GC tumor incidence data from reciprocal F1 progeny of matings between SWR and SJL mice reveal a strong maternal effect that may represent yet a third gene. These data support a heritable basis for GC tumorigenesis in the SWR model involving a small number of genes.

Alleles↗
PubMed1988

Induction of ovarian granulosa cell tumors in SWXJ-9 mice with dehydroepiandrosterone.

Spontaneous ovarian granulosa cell (GC) tumors develop in SWXJ-9 inbred mice at approximately the time of puberty. The effect of dehydroepiandrosterone (DHEA), a steroid secreted by the adrenals and reported to have antitumor actions, was examined in this ovarian tumor model. In contrast with expectations, administration of diet supplemented with 0.4% DHEA or Silastic capsules containing 10 mg DHEA resulted in a significant multifold increase in GC tumor incidence. Similar studies with metabolites of DHEA, i.e., testosterone (TESTO), dihydrotestosterone (DHT), and 17 beta-estradiol (E2), revealed that TESTO was as effective as DHEA in increasing GC tumor incidence. DHT was without effect, and E2 suppressed GC tumor incidence. Serum steroid levels and steroid target tissue responses were assessed to determine if a correlation between a change in level or response to specific steroids and GC tumorigenesis existed. In both tumor-free and GC tumor host mice, dietary or capsular treatment with DHEA, TESTO, or DHT resulted in substantial alteration in one or more of serum steroids, DHEA, androstenedione, TESTO, and DHT, in addition to the administered steroid. No consistent correlation was observed between changes in a single steroid or pattern of steroids and GC tumorigenesis. Although significant increases in serum estrogens could be detected in GC tumor hosts treated with DHEA but not TESTO, estrogens did not induce these tumors. Treatment with E2 increased only serum E2 levels. In tumor-free mice, DHEA and E2 treatments were associated with vaginal cytological evidence of estrogen action, whereas the androgens induced a leukocytic pattern. Eighty-eight % of GC tumor host mice, regardless of steroid treatment, showed a vaginal cytology pattern that included cornified cells. The evidence presented in this report leads us to hypothesize that (a) spontaneous and steroid-induced GC tumorigenesis in these mice have the same mechanism, and (b) subtle increases in DHEA or a closely related metabolite during the peripubertal period may initiate GC tumors in these genetically susceptible mice. The mechanism whereby these steroids initiate GC tumorigenesis remains to be determined.

Animals↗
PubMed1988

Mapping of mouse gamma crystallin genes on chromosome 1.

Restriction fragments analysis of DNA from mouse-hamster somatic-cell hybrid clones revealed that a mouse gamma crystallin cDNA hybridized to genomic sequences located on mouse chromosome 1. Identification of restriction fragment length polymorphisms (RFLPs) in the gamma crystallin sequences of inbred strains of mice permitted the further localization of the gamma crystallin genes (Cryg) to the proximal region of chromosome 1 closely linked to the loci encoding isocitrate dehydrogenase (Idh-1), a low molecular weight (LM) crystallin protein polymorphism (Len-1), and fibronectin (Fn-1). A single recombinant was observed between Len-1 and an RFLP in the gamma crystallin gene family, consistent with the hypothesis that Len-1 is one of the several structural loci encoding gamma crystallin genes. Len-1 is probably located on the centromeric end of the Cryg gene family. Linkage of Idh-1, Cryg, and Fn-1 in mice extends the syntenic relationship of those loci to the human, bovine, and rodent genomes and may define a chromosomal region that is generally conserved among mammals. The map position of Cryg, near the eye lens obsolescence (Elo) locus, was confirmed by the discovery that the restriction fragment patterns of gamma crystallin sequences differed between strain C3H/HeJ and the congenic anophthalmic mutant strain, C3H.Elo. Therefore, the gamma crystallin genes were cotransferred with the mutant Elo gene in the derivation of C3H.Elo. The results establish that LEN-1 is a marker for the gamma crystallin gene family, position the gamma crystallin gene family relative to other markers on mouse chromosome 1, and provide additional evidence that the Elo mutation is encoded at a locus closely linked to the gamma crystallin gene cluster. This study found no evidence of recombination hot spots within the gamma crystallin gene cluster.

Animals↗
PubMed1988

The hypothyroid (hyt/hyt) mouse: a model system for studying the effects of thyroid hormone on developmental changes in gene expression.

Thyroid hormone has been implicated as an important factor in rodent development. We have used a strain of mice with a recessive mutation producing congenital primary hypothyroidism (C.RF/J-hyt/+) to study the effects of thyroid hormone on developmental changes in the expression of genes encoding a number of proteins involved in lipid metabolism and transport. Total cellular RNA was prepared from the small intestine and liver of hyt/hyt mice and their unaffected littermates (+/?) at various times during postnatal development. RNA blots were probed with apolipoprotein A-I, A-II, A-IV, B, and E cDNAs plus cDNAs encoding the low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and three cytoplasmic hydrophobic ligand-binding proteins (two fatty acid-binding proteins and a protein that binds all-trans-retinol). Hypothyroidism results in small changes (1.5- to 5-fold) in the concentration of many of these mRNAs in liver and small intestine between postnatal days 15 and 50. A much greater tissue-specific effect was noted on apolipoprotein B (apoB) gene expression. In euthyroid +/? animals, apoB mRNA levels fall by a factor of 30 in liver between days 20 and 35 without a comparable decrease in the small intestine. This liver-specific decrease does not occur in hyt/hyt animals. The normal decrease in hepatic apoB mRNA levels is accompanied by a decrease in plasma apoB-100 but not apoB-48. No reduction in either form of plasma apoB was noted in hyt/hyt animals. Mutant hyt/hyt mice given thyroxine from birth to 35 days had liver apoB mRNA levels comparable to those in +/? littermates. In contrast, hepatic apoB mRNA concentrations did not fall to normal levels in hyt/hyt mice given thyroxine from postnatal days 15 to 35. All treatment groups have comparable levels of plasma corticosteroids. These data suggest that (i) there is a critical period or a required response time during postnatal development for thyroid hormone action on apoB gene expression, (ii) thyroid hormone's effect on apoB is tissue specific, and (iii) the hyt/hyt mouse represents a useful system to evaluate the developmental effects of thyroid hormone on specific gene expression.

Animals↗
PubMed1988

Juvenile spermatogonial depletion (jsd): a genetic defect of germ cell proliferation of male mice.

Adult C57BL/6J male mice homozygous for the mutant gene, juvenile spermatogonial depletion (jsd/jsd), show azoosper4ia and testes reduced to one-third normal size, but are otherwise phenotypically normal. In contrast, adult jsd/jsd females are fully fertile. This feature facilitated mapping the jsd gene to the centromeric end of chromosome 1; the gene order is jsd-Isocitrate dehydrogenase-1 (Idh-1)-Peptidase-3 (Pep-3). Analysis of testicular histology from jsd/jsd mice aged 3-10 wk revealed that these mutant mice experience one wave of spermatogenesis, but fail to continue mitotic proliferation of type A spermatogonial cells at the basement membrane. As a consequence, histological sections of testes from mutant mice aged 8-52 wk showed tubules populated by modest numbers of Sertoli cells, with only an occasional spermatogonial cell. Some sperm with normal morphology and motility were observed in epididymides of 6.5- but not in 8-wk or older mutants. Treatment with retinol failed to alter the loss of spermatogenesis in jsd/jsd mice. Analyses of serum hormones of jsd/jsd males showed that testosterone levels were normal at all ages--a finding corroborated by normal seminal vesicle and vas deferens weights, whereas serum follicle-stimulating hormone levels were significantly elevated in mutant mice from 4 to 20 wk of age. We hypothesize the jsd/jsd male may be deficient in proliferative signals from Sertoli cells that are needed for spermatogenesis.

Animals↗
PubMed1988

Growth hormone enhances hepatic epidermal growth factor receptor concentration in mice.

The effect of growth hormone (GH) on binding of epidermal growth factor (EGF) to liver membrane preparations was investigated in hypophysectomized mice and partially GH-deficient, genetic mutant "little" (lit/lit) mice. The EGF binding of normal male mice and testosterone-treated females was higher than in normal females. Due to diminished receptor concentration, hepatic EGF binding was decreased in male and female lit/lit mice to a level that was unaffected by gender or androgen treatment. GH replacement therapy by intermittent injections and continuous infusion restored the EGF binding of hypophysectomized mice to normal male and female levels, respectively, suggesting a role for the more pulsatile GH secretion in normal males. In lit/lit mice, however, both continuous and intermittent GH resulted in EGF binding levels comparable to those in normal females. In normal males continuous GH suppressed EGF binding. In conclusion, endogenous GH secretion induces EGF receptors in mice and this effect may be modulated by sex differences in GH secretion.

Animals↗
PubMed1988

Autoregulation of testicular LH receptors in Ames dwarf (df/df) and pigmy (pg/pg) mice.

The autoregulation of testicular LH receptors was studied in mutant mice with congenital PRL and GH deficiency (df/df) and in mutant mice with congenital resistance to GH (pg/pg). Low dose of hCG produced an increase in LH receptors in df/df mice, but not in normal mice of the same strain. Intermediate doses of hCG did not affect LH receptors in df/df mice, while decreasing them in normal mice. In pg/pg mice, hCG caused changes in LH receptors which were identical to those observed in their normal siblings. Comparison of these two mutations suggests a lack of involvement of GH in the regulation of testicular LH receptors. Moreover, results obtained from df/df mice could indicate the presence of direct effects of the df mutation on testicular LH receptors.

Animals↗
PubMed1987

Androgenic and estrogenic metabolites in serum of mice fed dehydroepiandrosterone: relationship to antihyperglycemic effects.

The steroid prehormone, dehydroepiandrosterone (DHEA) has potent antihyperglycemic effects when fed in the diet of genetically diabetic C57BL/KsJ-db/db mice. The purpose of this investigation was to analyze changes in sex steroid levels in serum of mice fed DHEA, and to compare the antihyperglycemic potencies of the various metabolites in order to clarify the mechanism of DHEA action. Steroid radioimmunoassays showed that dietary DHEA entered the blood in high concentrations and was actively metabolized to both androgens (testosterone, T; dihydrotestosterone, DHT) and estrogens (estrone, E1; 17 beta-estradiol, E2). This metabolism did not require intact adrenal glands or gonads. In C57BL/KsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in db/db males, DHEA feeding not only increased serum T and DHT, but also serum E1 and E2 levels. The db/db mice had increased amounts of adipose tissue that sequestered more intravenously injected 3H-E2; this additional body fat could account for increased aromatization of DHEA-derived estrogen precursors. Comparisons of the relative antihyperglycemic potencies of androgenic and estrogenic steroid metabolites of DHEA in db/db mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17 beta-E2 was effective by injection or per os, DHEA was effective only when administered per os, implicating alimentary tract conversion of DHEA to more biologically active reactants. Based on the pivotal position of DHEA as a prehormone for androgens, estrogens, and etiocholanolones, an explanation of the seemingly paradoxical effects exerted by this compound in blocking autoimmune disease, hyperglycemia, obesity, and neoplasia was proposed.

Androgens↗
PubMed1987

Mapping of the mouse fibronectin gene (Fn-1) to chromosome 1: conservation of the Idh-1-Cryg-Fn-1 synteny group in mammals.

Restriction fragment length polymorphisms (RFLPs) were observed in BamHI-digested mouse DNA probed with a cDNA for human fibronectin. Analysis of the inheritance of fibronectin RFLPs in AKXD and SWXJ recombinant inbred strains of mice mapped the locus, Fn-1, to the midregion of mouse chromosome 1 about 4 cM distal from the loci encoding gamma-crystallins (Cryg). Loci homologous to genes in the centromeric third of mouse chromosome 1 are also syntenic in rats, humans, and cattle and may, therefore, mark a large conserved chromosomal segment of the mammalian genome.

Animals↗
PubMed1987

Inherited congenital goiter in mice.

Congenital goiter (cog), a new autosomal recessive mutation in mice, has been mapped to the central region of chromosome 15. Young adult mutant mice are characterized by a reduced rate of growth, mild anemia, hypothyroidism, as indicated by significantly lower total serum T4 and T3, and elevated serum TSH. Thyroids from mutant mice are hypertrophied, deficient in colloid, show a reduced accumulation of iodine that is partially susceptible to perchlorate ion discharge, have modestly elevated serum immunoreactive thyroglobulin (Tg) levels, but are markedly deficient in glandular immunoreactive Tg content. Thyroid hormone therapy corrects the growth deficiency and prevents the thyroid hypertrophy resulting from excessive stimulation by TSH. These findings suggest that the cog mutant gene results in primary hypothyroidism in response to either defective synthesis or processing of Tg.

Aging↗
PubMed1986

Receptor-associated resistance to growth hormone-releasing factor in dwarf "little" mice.

Anterior pituitaries from the dwarf mouse strain "little" did not release growth hormone or accumulate adenosine 3',5'-monophosphate (cyclic AMP) in response to human and rat growth hormone-releasing factor (GRF). Dibutyryl cyclic AMP, as well as the adenylate cyclase stimulators forskolin and cholera toxin, markedly stimulated growth hormone (GH) release. The basis of the GH deficiency in the little mouse may therefore be a defect in an early stage of GRF-stimulated GH release related either to receptor binding or to the function of the hormone-receptor complex.

Animals↗
PubMed1986

Two loci affecting B cell responses to B cell maturation factors.

B lymphocytes from DBA/2Ha mice have a genetic defect characterized by a failure to differentiate into antibody-secreting cells in response to a family of lymphokines termed B cell maturation factors (BMFs). By contrast, B cells from DBA/2Ha mice respond normally in PFC assays to the B cell mitogen LPS, and macrophages from these mice are activated by one of the three BMFs. Two loci are responsible for the B cell defect in DBA/2Ha mice. One locus (Bmfr-1) is constitutively expressed throughout life, and maps approximately 13 cM distal to the brown locus on chromosome 4. A second locus (Bmfr-2) becomes active only after sexual maturity and is closely linked to the dilute locus on chromosome 9. At both loci, alleles determining responsiveness to BMFs are dominant over nonresponder alleles. The effect of Bmfr-2 on B cell responsiveness may be related to levels of the steroid sex hormones. DBA/2Ha mice offer a tool for studying the genetic and hormonal regulation of the immune system.

Age Factors↗