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Biomedical subjects

F Theuring

Publications and source records attributed to F Theuring.

At least 19 recordsLinked to original sources
PubMed2000

Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation.

The epidermal growth factor receptor (EGFR) is overexpressed in about 48% of human breast cancer tissues. To analyse the role of the EGFR in mammary tumor development we generated transgenic mice expressing the human EGFR under the control of either the MMTV-LTR (MHERc) or the beta-lactoglobulin promoter (BLGHERc). The BLGHERc-transgene was expressed exclusively in the female mammary gland, whereas the MHERc transgene was expressed more promiscuously in other organs, such as ovary, salivary gland and testis. Female virgin and lactating transgenic mice of both strains have impaired mammary gland development. Virgin EGFR transgenic mice developed mammary epithelial hyperplasias, whereas in lactating animals progression to dysplasias and tubular adenocarcinomas was observed. In both strains the number of dysplasias increased after multiple pregnancies. The transgene expression pattern was heterogeneous, but generally restricted to regions of impaired mammary gland development. Highest EGFR transgene expression was observed in adenocarcinomas. By using a whole mount organ culture system to study the differentiation potential of the mammary epithelium, we observed a reduced number of fully developed alveoli and a decrease in whey acidic protein expression. Taken together, EGFR overexpression results in a dramatic effect of impaired mammary gland development in vitro as well as in vivo, reducing the differentiation potential of the mammary epithelium and inducing epithelial cell transformation.

Animals↗
PubMed2000

Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice.

The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Animals↗
PubMed1998

The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system.

Neuregulins (NDF, heregulin, GGF ARIA, or SMDF) are EGF-like growth and differentiation factors that signal through tyrosine kinase receptors of the ErbB family. Here, we report a novel phenotype in mice with targeted mutations in the erbB2, erbB3, or neuregulin-1 genes. These three mutations cause a severe hypoplasia of the primary sympathetic ganglion chain. We provide evidence that migration of neural crest cells to the mesenchyme lateral of the dorsal aorta, in which they differentiate into sympathetic neurons, depends on neuregulin-1 and its receptors. Neuregulin-1 is expressed at the origin of neural crest cells. Moreover, a tight link between neuregulin-1 expression, the migratory path, and the target site of sympathogenic neural crest cells is observed. Sympathetic ganglia synthesize catecholamines in the embryo and the adult. Accordingly, catecholamine levels in mutant embryos are severely decreased, and we suggest that the lack of catecholamines contributes to the embryonal lethality of the erbB3 mutant mice. Thus, neuregulin-1, erbB2, and erbB3 are required for the formation of the sympathetic nervous system; the block in development observed in mutant mice is caused by a lack of neural crest precursor cells in the anlage of the primary sympathetic ganglion chain. Together with previous observations, these findings establish the neuregulin signaling system as a key regulator in the development of neural crest cells.

Animals↗
PubMed1998

Pathophysiology in endothelin-1 transgenic mice.

Transgenic mice expressing the human endothelin-1 (ET-1) were generated. These mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. Consequently, a progressive decrease in renal blood flow and/or glomerular filtration rate was observed, demonstrated by altered creatinine clearance and by magnetic resonance imaging. These genetically altered transgenic mice provide an interesting animal model in which to elucidate the role of ET-1 in the modulation of renal hemodynamics and glomerular and tubule functions.

Animals↗
PubMed1998

Apoptosis in kidneys of endothelin-1 transgenic mice.

Endothelin-1 (ET-1) transgenic mice are characterized by age-dependent development of renal cysts and renal fibrosis (interstitial fibrosis and glomerulosclerosis), leading to a progressive decrease in glomerular filtration rate. The mechanism causing the loss of functionally and morphologically normal renal tissue is unknown. An imbalance between cell proliferation and apoptosis in the kidneys of ET-1 transgenic mice might contribute to this process. We identified apoptotic cells in kidney sections by in situ end-labeling and by the typical nuclear chromatin morphology after propidium iodide (PI) staining. Cell proliferation was measured by estimating the proliferating cell nuclear antigen (PCNA)-positive cells. The numbers of apoptotic cells were significantly increased (p < 0.001) in the kidneys of 14-month-old ET-1 transgenic mice, whereas cell proliferation was not enhanced. Apoptotic cells were detected in the glomeruli, tubular cells, and renal interstitial cells in ET-1 transgenic mice. In conclusion, apoptotic loss of functional renal tissue appears to be associated with the progression of cyst formation and renal fibrosis. Therefore, an imbalance between cell proliferation and apoptosis could be an important cellular mechanism in ET-1 transgenic mice leading to end-stage kidney disease.

Animals↗
PubMed1997

Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

Animals↗
PubMed1997

Transgenic animals as models of neurodegenerative diseases in humans.

Neurodegenerative diseases are of major socioeconomic importance and represent an enormous challenge for the scientific and medical communities. Advances in molecular genetics during the past decade have begun to provide approaches for the establishment of animal models for these disorders using transgenic technology. Their analysis will lead to better understanding of disease pathogenesis and will be invaluable for the identification of novel diagnostic and therapeutic agents. With the current pace of genomic research, the generation of transgenic animal models, reproducing in full the pathology and symptoms of even complex disorders such as Alzheimer's disease, must now be considered achievable.

Alzheimer Disease↗
PubMed1996

Localization of large-T oncoprotein during the embryonic and fetal development of transgenic mice.

Oncoproteins are not only involved in the development of tumors but also play a role in physiological regulation in embryonic growth and differentiation. The mechanisms by which regulation is accomplished in embryonic stages differ from postnatal or adult stages. Oncoproteins responsible for tumors in the adult, i.e., products of proto-oncogenes, are prevented from causing tumors in the embryo. If oncogenes are introduced artificially into the embryo. will they be governed by the embryonic regulation described above? To answer this question we used transgenic mice in which the hybrid construct MSV-SV40-Large-T, composed of the Simian-Virus-Oncogene. Large-T with its SV40-promotor and the Moloney Murine Sarcoma Virus (MSV)-enhancer, had been integrated. Under the influence of large-T expression, these animals develop either brain or endocrine pancreas tumors. In the present investigation, we localised large-T expression during development of mouse embryos and fetuses. Interestingly, we saw large-T positive reactions in organ anlagen other than those that later develop tumors. We found large-T antigens in cartilage anlagen, e.g., in ribs and vertebrae, particularly in fetuses of days 14 to 17, and also in a variety of epithelial cells such as in the lung or the choroid plexus. Our results indicate that, as for proto-oncogene products, the effect of an artificially introduced transgenic oncogene product can also be regulated by embryonic cells.

Animals↗
PubMed1994

Purification of human big endothelin 1 derived through cleavage with collagenase and dipeptidylpeptidase IV from a fusion protein expressed in Escherichia coli.

The cDNA coding for human big endothelin 1 (bigET-1), preceded by an optimized collagenase recognition sequence and followed by a stop codon, was fused in frame to the C-terminal region of alkaline phosphatase (AP). The fusion protein (AP-bigET), expressed in Escherichia coli K12 upon the lowering of organic phosphate concentrations, consisted of alkaline phosphatase (1-447), the collagenase cleavage site (Gly-Pro-Ala)4, and glycylprolyl-bigET-1. AP-bigET accumulated intracellularly in the form of inclusion bodies that were extensively washed and finally extracted by 8 M urea to yield highly enriched AP-bigET. Upon digestion of the fusion protein with collagenase, two disulfide conformeres of glycylprolyl-bigET-1 (bigET-1A and bigET-1B) could be purified by reverse-phase FPLC. Upon treatment with dipeptidylpeptidase IV to remove the N-terminal glycylprolyl-dipeptide, the later-eluting form of bigET-1 (bigET-1B) coeluted with authentic human bigET-1 on reverse-phase HPLC. BigET-1A and bigET-1B were formed at a ratio of 1:3. After reduction and S-pyridylethylation, both conformers coeluted with authentic but reduced bigET-1. Their amino acid sequences were identical. Both forms were converted by digestion with pepsin to the respective ET-1 conformeres (ET-1A and ET-1B) that were purified. In vasoconstriction assays, ET-1B but not ET-1A, at 10(-8) M, evoked a maximal response indistinguishable from that of authentic ET-1.

Alkaline Phosphatase↗
PubMed1994

Improved in situ beta-galactosidase staining for histological analysis of transgenic mice.

The present study describes a novel method for the histochemical demonstration of beta-galactosidase activity on tissue sections. We have replaced 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-Gal) with 5-bromo-indolyl-beta-o-galactopyranoside (Bluo-Gal) as a chromogenic substrate for the bacterial beta-galactosidase (lacZ). After beta-galactosidic cleavage, Bluo-Gal precipitates in form of fine birefringent crystals, whereas X-gal gives rise to an amorphous precipitate. Upon microscopic examination under polarized light, the crystals emit a strong signal consisting of yellow reflected light. This property of Bluo-Gal results in greatly enhanced sensitivity of the staining method for beta-galactosidase and allows for optimal morphological resolution. To exemplify the applications of this technique, the expression is demonstrated in transgenic mice of beta-galactosidase driven by a fragment of the human tissue-type plasminogen activator promoter.

Animals↗
PubMed1994

Primary mesenchymal tumors of the urinary bladder. A histological and immunohistochemical study of 30 cases.

The light microscopic and immunohistochemical features of 30 primary mesenchymal neoplasms of the urinary bladder are reported. Half of the cases represented smooth and striated muscle tumors (five leiomyomas, seven leiomyosarcomas including epithelioid and myxoid subtypes, one rhabdomyoma, one embryonal rhabdomyosarcoma and one alveolar rhabdomyosarcoma). One third of the tumors were of fibrohistiocytic origin (one fibrous histiocytoma and eight malignant fibrous histiocytomas including fascicular and storiform, inflammatory and pleomorphic subtypes). In addition, a malignant epithelioid schwannoma, a round cell liposarcoma, two hemangiomas and two mixed mesodermal tumors were observed. The morphology of the vesical mesenchymal tumors was identical to that of their counterparts known to occur in other sites, particularly in the soft tissue. Muscle-specific actin, alpha-1-antichymotrypsin, S-100-protein and neuron-specific enolase proved to be useful and reliable immunomarkers for differential diagnosis of poorly differentiated leio- and rhabdomyosarcomas, malignant fibrous histiocytomas and malignant schwannomas. Since some tumors coexpressed several classes of intermediate filaments, diagnostic immunocytochemistry should only be used considering a larger panel of antibodies and in close correlation with the histological and cytological features of the neoplasms.

Adolescent↗
PubMed1994

Molecular phenotype of simian virus 40 large T antigen-induced primitive neuroectodermal tumors in four different lines of transgenic mice.

BACKGROUND: We compared the molecular phenotypes of central nervous system tumors arising in four different lines of transgenic mice (TGM) carrying the Simian virus 40 large T antigen driven by different promoters or enhancers. Two of the four lines developed primitive neuroectodermal tumors (PNETs) in the brain stem or pineal gland. A third TGM line developed retinoblastomas (a PNET-like tumor of the retina) as well as PNETs in the mesencephalon, while the fourth TGM developed retinoblastomas and adrenal pheochromocytomas. EXPERIMENTAL DESIGN: The expression of developmentally regulated polypeptides specific for the neuronal or glial lineage was examined in these PNETs using immunohistochemistry and Western blotting. RESULTS: Neoplastic cells in all of the PNETs exhibited neuronal, but no glial specific markers as evidenced by the invariable expression of synaptophysin, but no detectable glial fibrillary acidic protein or myelin basic protein. PNETs with a more differentiated neuronal phenotype expressed multiple neuronal polypeptides. The phenotypic properties of these PNETs closely resembled those found in human brain PNET biopsy samples and cell lines derived therefrom. CONCLUSIONS: We conclude that Simian virus 40 T antigen-induced PNETs in TGM exhibit the molecular phenotype of developing neurons or neuronal progenitor cells. Although many factors could influence the phenotype of these experimental PNETs (e.g., promoter, site of integration of the transgene) these PNETs appear to be suitable TGM models of human PNETs of the central nervous system.

Adrenal Gland Neoplasms↗
PubMed1993

Transcripts for cysteine-rich secretory protein-1 (CRISP-1; DE/AEG) and the novel related CRISP-3 are expressed under androgen control in the mouse salivary gland.

Expression of the gene for cysteine-rich secretory protein-1 (CRISP-1), the counterpart of the rat sperm-coating protein DE/AEG, was evidenced in male mouse salivary gland by both isolation of the corresponding cDNA clone and RNA blot analysis. In addition, the cDNA coding for the new related CRISP-3, which shares 77% amino acid identity with CRISP-1, was isolated from a salivary gland cDNA library. The activity of CRISP-1 and -3 genes in mouse salivary gland is strongly androgen dependent, as seen in castrated males; also, no CRISP-1 and only weak CRISP-3 expression was detected in female salivary gland. A variety of tissues were tested for the presence of CRISP-3 transcripts, but specific signals were only found in salivary gland. The results of genomic DNA blot analysis are compatible with the existence of single discrete genes for CRISP-1 and CRISP-3.

Amino Acid Sequence↗
PubMed1993

[Tumor-like and preneoplastic lesions as well as low risk and high risk urothelial tumors].

In its first part the review deals with all known hyperplastic, metaplastic as well as dysplastic urothelial changes and discusses their possible preneoplastic nature. The various changes are classified as indirect, facultative and obligatory premalignant lesions. In its second part, the review considers the tumor-like growths. In particular, it focuses on the pseudotumorous effects of various urocystitis types, postoperative spindle cell pseudosarcoma, glandular and nephrogenic metaplasias, malakoplakia and some tissue heterotopias and malformations. In its last part, the review critically compares the classification principle of the urothelial neoplasias into low-risk and high-risk tumors with other tumor classifications (superficial carcinoma/low-grade and high-grade tumors). The significance of recent study results for assessing the risk of urothelial carcinomas is discussed.

Carcinoma, Transitional Cell↗
PubMed1993

Endocrine pancreatic tumors in MSV-SV40 large T transgenic mice.

Mice carrying a Moloney murine sarcoma virus-(MSV) simian virus 40 large T transgene develop heritable tumors including endocrine pancreatic tumors. We have established several independent transgenic mouse lines expressing this transgene. One of these lines, designated MSV125, is characterized by the development of congenital cataracts and either pancreatic or brain tumors. The development and histopathology of the pancreatic tumors were studied by light microscopy and immunocytochemistry for large T antigen, neuron-specific enolase, insulin, proinsulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, and serotonin. The 23 tumors examined were similar to human endocrine pancreatic tumors with respect to their macroscopic and histological features. We classified 91% of the tumors as insulinomas based on the predominance of insulin immunoreactivity. In newborn and young transgenic animals, nesidioblastosis and islet cell proliferation, consisting mostly of insulin containing beta cells, was obvious and persisted into adulthood. In transgenic animals more than 2 months old, islet hyperplasia and dysplasia predominated from which single tumors developed. Hyperplastic and dysplastic islets were composed mostly of beta cells. Large T antigen was detectable not only in tumor cells, but also in cells of normal and hyperplastic islets and in islet anlagen of newborn transgenic mice, indicating expression of the transgene in the endocrine part of the pancreas. Large T antigen-immunoreactivity was restricted to the beta cells. Insulinomas of the MSV-simian virus 40 T antigen-derived MSV125 transgenic mouse line may represent a valuable model for the study of the development and biology of insulinoma.

Animals↗
PubMed1992

Midline brain tumors in MSV-SV 40-transgenic mice originate from the pineal organ.

Adult transgenic mice expressing the large T-antigen of the Simian virus 40 (SV 40) under the control of the Moloney murine sarcoma virus (MSV) enhancer and the SV 40 promoter develop inheritable uniform midline brain neoplasms showing features of primitive neuroectodermal tumors. The origin and histogenesis of these tumors were investigated in the present study. The brain and pineal organ of fetal and young transgenic mice less than 3 months old displayed normal macroscopic and microscopic features. In 3.5-month-old animals, the pineal organ was considerably enlarged due to hyperplasia, finally leading to tumor formation. Immunocytochemical demonstration of large T-antigen showed that this oncoprotein was already expressed in the nuclei of certain cells in the pineal organ of fetuses (16 and 18 days old) and newborn animals, but was absent from all other parts of the brain. The immunocytochemical demonstration of S-antigen (arrestin), a highly characteristic marker for pinealocytes, was used for further characterization of the large T-antigen-immunoreactive cells. The fetal pineal organ did not contain immunoreactive S-antigen. This first occurred in certain pinealocytes of newborn mice. Double immunostaining revealed that in newborn and older transgenic mice the immunoreactive large T-antigen was exclusively found in nuclei of cells containing S-antigen immunoreaction in their cytoplasm. Thus, transformed pinealocytes appear as stem cells of the experimental tumors. The results of this study suggest that primitive neuroectodermal tumors and the normal tissue from which they originate share certain molecular and immunocytochemical features.

Animals↗
PubMed1991

Eye pathology in transgenic mice carrying a MSV-SV 40 large T-construct.

Several lines of transgenic mice carrying a transgene construct consisting of the regulatory enhancer element of the Moloney murine sarcoma virus and the Simian virus 40 genome coding for the SV 40 promoter and the large T antigen were established. We describe several abnormalities found in the eyes of transgenic animals of which heritable cataract formation, probably due to disturbances in primary lens fibre differentiation, showed a close correlation to large T antigen expression. Additionally, lenticonus anterior, retinal dysplasia and one case of malignant transformation of lens epithelium were found. The introduction of the deleted MSV-enhancer linked to the large T coding region led to less severe postnatally occurring cataracts. Thus, the partial deletion of the MSV enhancer resulted in differences in the degree of severity of lens disturbances. However, tissue specificity remained constant. Our results indicate that large T antigen seems to play an important role in cataract formation but not in the pathogenesis of retinal dysplasia.

Animals↗