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J E Wilkinson

Publications and source records attributed to J E Wilkinson.

At least 19 recordsLinked to original sources
PubMed2004

Skeletal dysplasia and male infertility locus on mouse chromosome 9.

In mice and humans, growth insufficiency and male infertility are common disorders that are genetically and phenotypically complex. We describe a spontaneously arising mouse mutant, chagun, that is affected by both dwarfism and male infertility. Dwarfism disproportionately affects long bones and is characterized by a defect in the proliferative zone of chondrocytes in the growth plate. Gonads of mutant males are small, with apparent germ cell loss and no evidence of mature sperm. The locus responsible for chagun is recessive and maps to distal chromosome 9, in a region homologous to human chromosome 3. This location is consistent with chagun defining a novel locus. Identification of the mutant gene will uncover the basis for another type of skeletal dysplasia and male infertility.

Animals↗
PubMed2001

Phenotypic variations of orpk mutation and chromosomal localization of modifiers influencing kidney phenotype.

The Oak Ridge polycystic kidney (orpk) mutant mouse model resulted from a transgene insertion into the Tg737 gene and exhibits a pleiotropic syndrome with lesions in the kidney, liver, and pancreas. We found marked differences in the phenotypic expression of the orpk mutation when bred on different genetic backgrounds. In the FVB/N background, the phenotype is very severe for kidney, pancreas, and liver lesions. To evaluate better how genetic background might influence the expressivity of the orpk phenotype, we bred the transgene into the C3HeB/FeJLe (C3H) genetic background. We performed a genome-wide scan using backcross and intercross populations with more than 150 markers to map the chromosomal location of the modifier genes that differ in the FVB/N and C3H genetic backgrounds that affect the severity of kidney disease in the orpk mouse. Low-resolution interval mapping was performed using the Map Manager QTb program, with the interval explaining a significant portion of the variance being the distal end of chromosome 4.

Animals↗
PubMed2001

The murine mutation scurfy (sf) results in an antigen-dependent lymphoproliferative disease with altered T cell sensitivity.

The scurfy (sf) murine mutation results in a rapidly fatal lymphoproliferative disease, causing death by 26 days. Mature CD4+ T cells which tested hyperresponsive to T cell receptor (TCR) stimulation are involved. When sf was bred onto a transgenic line (DO11.10) in which 75 - 95 % of the T cells express TCR for ovalbumin (OVA) 323 - 339, sf / Y OVA mice had prolonged lifespans and less severe clinical symptoms compared to controls. However, sf / Y OVA mice eventually developed disease and died with manifestations similar to those of the original sf strain. The Rag1 knockout (KO) mouse, which cannot produce mature T (or B) cells without the addition of functional transgenes, was chosen for further breeding. The combination of Rag1 KO, the OVA transgene, and sf produced mice with 100 % of their mature DO11.10 alpha beta T cells reactive strictly to OVA peptide. None of these Rag1 - / - sf / Y OVA mice developed the scurfy disease. They retained central deletion capability in vivo, but demonstrated an altered in vitro response to OVA peptide. These results indicate that mice without TCR for endogenous antigens do not develop scurfy symptoms, and are consistent with the hypothesis that the sf mutation requires antigen stimulation to manifest disease, perhaps via altered TCR sensitivity.

Abatacept↗
PubMed2001

Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.

Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16-25 days after birth, and is characterized by overproliferation of CD4+CD8- T lymphocytes, extensive multiorgan infiltration and elevation of numerous cytokines. Similar to animals that lack expression of either Ctla-4 or Tgf-beta, the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8- T-cell activity. Here we identify the gene defective in sf mice by combining high-resolution genetic and physical mapping with large-scale sequence analysis. The protein encoded by this gene (designated Foxp3) is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.

Amino Acid Motifs↗
PubMed2001

Sequence analysis of a 101-kilobase plasmid required for agar degradation by a Microscilla isolate.

An agar-degrading marine bacterium identified as a Microscilla species was isolated from coastal California marine sediment. This organism harbored a single 101-kb circular DNA plasmid designated pSD15. The complete nucleotide sequence of pSD15 was obtained, and sequence analysis indicated a number of genes putatively encoding a variety of enzymes involved in polysaccharide utilization. The most striking feature was the occurrence of five putative agarase genes. Loss of the plasmid, which occurred at a surprisingly high frequency, was associated with loss of agarase activity, supporting the sequence analysis results.

Agar↗
PubMed2000

Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous in transgenic line TgN3261Rpw.

Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous are congenital ocular anomalies that can lead to cataract formation. A line of insertional mutant mice, TgN3261Rpw, generated at the Oak Ridge National Laboratory in a large-scale insertional mutagenesis program was found to have a low incidence (8/243; 3.29%) of multiple developmental ocular abnormalities. The ocular abnormalities include persistent hyperplastic primary vitreous, persistent hyperplastic tunica vasculosa lentis, failure of cleavage of the anterior segment, retrolental fibrovascular membrane, posterior polar cataract, and detached retina. This transgenic mouse line provides an ontogenetic model because of the high degree of similarity of this entity in humans, dogs, and mice.

Animals↗
PubMed1999

Cellular and molecular characterization of the scurfy mouse mutant.

Mice hemizygous (Xsf/Y) for the X-linked mutation scurfy (sf) develop a severe and rapidly fatal lymphoproliferative disease mediated by CD4+CD8- T lymphocytes. We have undertaken phenotypic and functional studies to more accurately identify the immunologic pathway(s) affected by this important mutation. Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfy T cells. Scurfy T cells also exhibit strong up-regulation of cell surface Ags indicative of in vivo activation, including CD69, CD25, CD80, and CD86. Both scurfy and normal T cells are responsive to two distinct signals provided by the TCR and by ligation of CD28; scurfy cells, however, are hyperresponsive to TCR ligation and exhibit a decreased requirement for costimulation through CD28 relative to normal controls. This hypersensitivity may result, in part, from increased costimulation through B7-1 and B7-2, whose expression is up-regulated on scurfy T cells. Although the specific defect leading to this hyperactivation has not been identified, we also demonstrate that scurfy T cells are less sensitive than normal controls to inhibitors of tyrosine kinases such as genistein and herbimycin A, and the immunosuppressant cyclosporin A. One interpretation of our data would suggest that the scurfy mutation results in a defect, which interferes with the normal down-regulation of T cell activation.

Abatacept↗
PubMed1998

Epidermal growth factor receptor activity mediates renal cyst formation in polycystic kidney disease.

A consistent phenotype observed in both human patients and several different mouse models of autosomal recessive polycystic kidney disease (ARPKD) is an increased activity of the epidermal growth factor receptor (EGFR) in the affected kidneys. To determine whether this increased activity of the EGFR is a functional event that is directly part of the disease pathway of renal cyst formation, we used a genetic approach to introduce a mutant EGFR with decreased tyrosine kinase activity into a murine model of ARPKD. We found that the modified form of the EGFR could block the increase in EGFR-specific tyrosine kinase activity that normally accompanies the development of renal cysts, and this correlated with an improvement in kidney function and a substantial decrease in cyst formation in the collecting ducts. These results suggest that changes in the expression of the EGFR contribute to the formation of cysts in the collecting ducts, and that drugs that target the tyrosine kinase activity of the EGFR may potentially be therapeutic in ARPKD.

Animals↗
PubMed1998

Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.

We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow mutation (A(vy)) of the mouse agouti gene which regulates coat color pigmentation by acting within the micro-environment of the hair follicle has been shown to function as a tumor promoter in the liver, we hypothesized that it may also play a role in TGxAC skin tumorigenesis. Endogenous agouti protein product was detected in the outer root sheath of anagen hair follicles following plucking of the hair shaft, but not in the interfollicular epithelium, in TGxAC mice on an FVB/N genetic background. It was also detected in papillomas from these mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking. Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line results in an approximately 2-fold increase in papilloma development compared with controls which did not carry the A(vy) allele following twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition, TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of humoral hypercalcemia mediated by parathyroid hormone-related protein (PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus, we conclude that the A(vy) allele can influence the development of skin tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.

Agouti Signaling Protein↗
PubMed1998

Vesicular and ulcerative dermatopathy resembling superficial necrolytic dermatitis in captive black rhinoceroses (Diceros bicornis).

The histopathology, clinical presentation, and epidemiology of a cutaneous and oral mucosal disease affecting 40 black rhinoceroses (Diceros bicornis) at 21 zoological parks (50% of the captive US population) were investigated. Twenty-seven biopsies were examined from recent lesions, and clinical information was available from 127 episodes. The cutaneous lesions began as plaques that progressed to vesicles, bullae, or ulcers. Lesions waxed and waned in individual cases. Lesions were predominantly bilaterally symmetrical, affecting pressure points, coronary bands, tips of the ears and tail, and along the lateral body wall and dorsum. Oral lesions were first noticed as ulcers and were present on the lateral margins of the tongue, palate, and mucocutaneous junctions of the lips. All recent lesions had similar histopathologic findings of prominent acanthosis, hydropic degeneration of keratinocytes in the stratum spinosum, spongiosis, intraepithelial vesicles, and parakeratosis without dermal inflammation. Chronic lesions were ulcerated. No pathogens were identified by culture or electron microscopy. Most episodes coincided with stress events (transportation, sudden cold temperatures, intraspecific harassment, estrus, advanced pregnancy) or concurrent diseases (toxic hepatopathy, hemolytic anemia, respiratory or urinary tract infections). Affected rhinoceroses usually were lethargic and had weight loss. Affected rhinoceroses also had lower hematocrit, serum albumin, and cholesterol values than captive healthy or wild rhinoceroses. The clinical patterns and histopathologic findings are similar to those of superficial necrolytic dermatitis in dogs and necrolytic migratory erythema in humans. The high prevalence of this skin disease in captive black rhinoceroses under many circumstances suggests that their epidermis is acutely sensitive to any disruption of metabolic homeostasis. We propose that metabolic changes secondary to a stress response from maladaptation or nutritional inadequacy of captive diets may contribute to the development of this disease in rhinoceroses without hepatopathies.

Animals↗
PubMed1998

Characterization of growth factor responsiveness and alterations in growth factor homeostasis involved in the tumorigenic conversion of mouse oval cells.

Five mouse oval cell lines were investigated in regards to their growth and differentiation factor (GDF) responsiveness and to changes in their GDF responsiveness following tumorigenic conversion. In all 59 GDFs and 11 comitogens were evaluated with variable responsiveness, depending on the mouse oval cell line under study, observed. Analysis of oval cell GDF responsiveness during tumorigenic conversion revealed that tumorigenic variants displayed alterations in GDF responsiveness which correlated with tumorigenicity. In addition, analysis of autocrine/paracrine growth factor production demonstrates that most tumorigenic variants produce growth factors. These studies demonstrate for the first time that (1) mouse oval cells respond to a wide variety of GDFs including various members of the interleukin, chemokine, stem cell factor, EGF, FGF, PDGF, TGF-beta, VEGF, insulin, CSF, TNF, HGF, and IFN growth and differentiation factor families in addition to multiple comitogens and (2) during tumorigenic conversion mouse oval cells undergo alterations which result in both alterations in GDF responsiveness and the autocrine/paracrine production of multiple GDFs.

Animals↗
PubMed1997

The tetratricopeptide repeat containing Tg737 gene is a liver neoplasia tumor suppressor gene.

The Tg737 gene was investigated for gross alterations in a series of rodent/human liver tumors and human tumorigenic cell lines. The Tg737 gene was found to be altered in approximately 40% of the rodent chemically-induced liver tumors, 40% of the human liver tumors, and in liver, kidney and pancreatic human tumor cell lines. Ectopic re-expression of the Tg737 gene in a Tg737 deleted mouse liver tumor cell line resulted in suppression of tumorigenic growth, without altering in vitro cell culture growth. Treatment of mice which are either homozygous normal or heterozygous deleted at the Tg737 locus with the carcinogen diethylnitrosamine resulted in an increase in preneoplastic foci formation in the Tg737 heterozygous deleted mice. Ectopic expression of the Tg737 gene results in multinucleated cells, loss of Tg737 gene expression results in the proliferation of liver stem cells (oval cells) without concomitant differentiation, and reexpression of the Tg737 gene reestablished responsiveness to external differentiation factors. We believe this is the first report demonstrating tumor suppression activity for a tetratricopeptide repeat gene family member and provides insights into the function of this family of genes in mammalian cells.

Animals↗
PubMed1997

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity.

The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

Adipose Tissue↗
PubMed1997

Efficacy of taxol in the orpk mouse model of polycystic kidney disease.

Polycystic kidney disease (PKD) a is common disease in the human population that can lead to renal failure and death. Taxol has recently been reported to be of therapeutic benefit in the cpk mouse model of PKD. To determine whether these results also apply to other models of PKD, we studied the effects of taxol treatment on the development of renal cysts and biliary hyperplasia/dysplasia/fibrosis in the orpk mouse mutant, a unique murine model for human autosomal recessive PKD. We report no significant differences between the treatment and control groups with respect to weight gain, survival, urine to serum osmolality ratio, and serum concentration of liver enzymes. Moreover, renal cystic development was not affected by taxol treatment in the orpk mutant animals. This was confirmed by lectin staining and morphometric analysis of the renal cysts, which indicated no significant differences between treatment groups. Therefore, while taxol has a positive effect on the cystic kidney disease in cpk mutant mice, this effect is not applicable to all forms of PKD.

Aging↗
PubMed1997

A study of forty-nine consecutive Whipple resections for periampullary adenocarcinoma.

BACKGROUND: We designed a program to evaluate the morbidity, mortality, survival rates, and patient's quality of life after Whipple resection for pancreatic and other periampullary adneocarcinoma. PATIENTS AND METHODS: After studying 11 fresh and unembalmed cadavers to learn the regional anatomy and to practice the surgical techniques for traditional Whipple procedure by the senior author (JS), 49 patients aged 56 to 84 years old were treated with Whipple's pancreatoduocenectomy. RESULTS: There was no postoperative mortality or morbidity from anastomotic leakage. All 49 patients were discharged in an improved condition following surgery, including 5 patients with emergency resection. Eight patients are alive at the time of this writing, including 2 patients who had their pancreatic cancer resected 168 and 139 months ago. CONCLUSIONS: In the opinion of these authors, treatment of all resectable cancers with Whipple's pancreatoduodenectomy offers not only a superior palliation but also the hope of cure.

Adenocarcinoma↗
PubMed1997

The role of the agouti gene in the yellow obese syndrome.

The yellow obese syndrome in mice encompasses many pleiotropic effects including yellow fur, maturity-onset obesity, hyperinsulinemia, insulin resistance, hyperglycemia, increased skeletal length and lean body mass, and increased susceptibility to neoplasia. The molecular basis of this syndrome is beginning to be unraveled and may have implications for human obesity and diabetes. Normally, the agouti gene is expressed during the hair-growth cycle in the neonatal skin where it functions as a paracrine regulator of pigmentation. The secreted agouti protein antagonizes the binding of the alpha-melanocyte-stimulating hormone to its receptor (melanocortin 1 receptor) on the surface of hair bulb melanocytes, causing alterations in intracellular cAMP levels. Widespread, ectopic expression of the mouse agouti gene is central to the yellow obese phenotype, as demonstrated by the molecular cloning of several dominant agouti mutations and the ubiquitous expression of the wild-type agouti gene in transgenic mice. Recent experiments have revealed that the hypothalamus and adipose tissue are biologically active target sites for agouti in the yellow obese mutant lines.

Agouti Signaling Protein↗
PubMed1997

The combination of epidermal growth factor and transforming growth factor-beta induces novel phenotypic changes in mouse liver stem cell lines.

Mouse liver stem cell (oval cell) lines were investigated in order to determine the role which two families of growth and differentiation factors (GDFs), epidermal growth factor (EGF) family and transforming growth factor beta (TGF-beta) family, play in liver regeneration. EGF family members, including EGF, amphiregulin, betacellulin, heparin-binding epidermal growth factor, and TGF-alpha, were mitogenic for oval cell lines while TGF-beta family members, including TGF-beta1, TGF-beta2 and TGF-beta3, inhibited mitogenesis and induced apoptosis in oval cell lines. Surprisingly, the combination of EGF family members and TGF-ss family members resulted in neither proliferation nor apoptosis but instead in a novel cellular response, cellular scattering in tissue culture and morphological differentiation in Matrigel. Analysis of the signal transduction pathways activated by exposure of oval cell lines to either EGF, EGF+TGF-beta, or TGF-beta indicated that novel combinations of intracellular signals result following stimulation of the cells with the combination of EGF+TGF-beta. These data reveal that the dynamics of synergistic GDF action following tissue injury and regeneration results in a new level of complexity not obvious from the study of individual GDFs.

Animals↗