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Sympathetic hyperplasia and neuroblastomas in transgenic mice expressing polyoma middle T antigen
A Aguzzi1, E F Wagner, R L Williams
1Laboratory of Neuropathology, University Hospital, Zürich, Switzerland.
Abstract:
Transgenic mice carrying a cDNA to the polyoma virus middle T (mT) antigen linked to the thymidine kinase promoter were generated to study the consequences of deregulated expression of mT-associated tyrosine kinase activity in a wide variety of tissues. Four independent transgenic founder animals were obtained, from one of which was established a transgenic line. This mouse and all its offspring developed multiple neuroblastomas between 2 and 3 months of age. Expression of the transgene (assayed by tyrosine kinase assay and in situ hybridization) was restricted to the neurons of the central and peripheral nervous tissue, probably because of a positional effect of the transgene integration. Characteristic preneoplastic lesions in the sympathetic ganglia and in the adrenal medulla were identified from which the neuroblastomas originated. The tumors arising in these mice show striking analogies to human neuroblastomas, including the sites of development of the tumors, their histological and ultrastructural appearance, and the expression of diagnostic markers, such as synaptophysin, and high expression of the N-myc oncogene. This animal model thus provides a unique tool for studying growth control in sympathetic neuroblasts and the pathogenesis of neuroblastoma.
Insights
Researchers created transgenic mice with polyoma virus middle T antigen to study neuroblastomas. These mice developed tumors similar to human neuroblastomas, offering a valuable model for research.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Deregulated tyrosine kinase activity is implicated in various cancers.
- The polyoma virus middle T (mT) antigen is a potent activator of tyrosine kinases.
Purpose of the Study:
- To investigate the consequences of deregulated mT-associated tyrosine kinase activity in vivo.
- To establish a transgenic mouse model for studying neuroblastoma pathogenesis.
Main Methods:
- Generation of transgenic mice carrying the polyoma virus mT antigen under the control of the thymidine kinase promoter.
- Analysis of transgene expression using tyrosine kinase assays and in situ hybridization.
- Histological, ultrastructural, and molecular characterization of tumors.
Main Results:
- A transgenic line developed spontaneous neuroblastomas in offspring between 2 and 3 months of age.
- Transgene expression was localized to neuronal tissues, suggesting a positional effect.
- Tumors exhibited striking similarities to human neuroblastomas, including N-myc oncogene overexpression.
Conclusions:
- The established transgenic mouse model closely mimics human neuroblastoma.
- This model serves as a valuable tool for investigating neuroblastoma development and therapeutic strategies.