Meningiomas are tumors of the meninges, the delicate membranes that cover the surface of the brain and spinal cord (most commonly known as the site of inflammation during meningitis). Although the majority of meningiomas are benign, a portion are malignant and associated with significant morbidity.
Meningiomas can occur spontaneously, or they can be associated with a hereditary disorder called neurofibromatosis type 2. Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene, a tumor suppressor gene whose disruption facilitates the development of cancer. However, both sporadic and familial cases of meningioma development are often associated with mutations in the NF2 gene.
Dr. Giovannini and colleagues used innovative DNA technology to mimic human meningioma development in mice. In humans, meningiomas arise from specific cells within the meninges, called arachnoidal cells. Dr. Giovannini and colleagues used a gentically engineered viral system to inactivate the NF2 gene in the arachnoidal cells of newborn mice.
The researchers generated a strain of mice that contain a specific DNA sequence called a loxP site on either side of a critical region in the NF2 gene. loxP sites are naturally found in viruses that infect bacteria (bacteriophages), where they are recognized by an enzyme, Cre. Cre deletes the intervening DNA between the loxP sites. This Cre-lox technology enables scientists to effectively edit DNA by flanking their gene of interest with loxP sites, and then introducing Cre to cut out the gene.
To introduce Cre into arachnoidal cells, Dr. Giovannini and colleagues genetically engineered an adenovirus to carry the Cre gene. Adenoviruses cause various illnesses in humans, like upper respiratory tract infections and gastroenteritis, but they are commonly used by scientists as vectors, or vehicles, to introduce foreign DNA into a cell. By injecting Cre-containing adenovirus into the cerebrospinal fluid of newborn mice, they were able to infect arachnoidal cells with the engineered virus and thereby introduce the Cre enzyme into these cells.
Adenoviral delivery of Cre into the arachnoidal cells of mice with a loxP-flanked NF2 gene resulted in the inactivation of NF2 in these cells. The researchers tracked the development of these NF2-deficient mice and found that by four months of age 30% of the mice developed meningiomas similar to human tumors. These results demonstrate that NF2 loss is sufficient for meningioma formation.
In addition to providing novel insight into the role of NF2 in meningioma formation, Dr. Giovannini’s work demonstrates, for the first time, that adenoviral delivery of Cre can be successfully used in the central nervous system. The animal model they have developed with this technology will enable scientists to study the development and progression of meningiomas, and ultimately provide a forum to test the utility of potential therapies.
Journal
Genes & Development