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Neoplasia. Nov 2002; 4(6): 501–509.
PMCID: PMC1503664

Detection of Spontaneous Schwannomas by MRI in a Transgenic Murine Model of Neurofibromatosis Type 21


Spontaneous schwannomas were detected by magnetic resonance imaging (MRI) in a transgenic murine model of neurofibromatosis type 2 (NF2) expressing a dominant mutant form of merlin under the Schwann cell-specific P0 promoter. Approximately 85% of the investigated mice showed putative tumors by 24 months of age. Specifically, 21% of the mice showed tumors in the intercostal muscles, 14% in the limb muscles, 7% in the spinal cord and spinal ganglia, 7% in the external ear, 14% in the muscle of the abdominal region, and 7% in the intestine; 66% of the female mice had uterine tumors. Multiple tumors were detected by MRI in 21% of mice. The tumors were isointense with muscle by T1-weighted MRI, showed strong enhancement following administration of gadolinium-DTPA, and were markedly hyperintense by T2-weighted MRI, all hallmarks of the clinical manifestation. Hematoxylin and eosin staining and immunohistochemistry indicated that the tumors consisted of schwannomas and Schwann cell hyperplasias. The lesions stained positively for S-100 protein and a marker antigen for the mutated transgenic NF2 protein, confirming that the imaged tumors and areas of hyperplasia were of Schwann cell origin and expressed the mutated NF2 protein. Tumors were highly infectable with a recombinant herpes simplex virus type 1 vector, hrR3, which contains the reporter gene, lacZ. The ability to develop schwannoma growth with a noninvasive imaging technique will allow assessment of therapeutic interventions.

Keywords: magnetic resonance imaging, transgenic mice, neurofibromatosis, herpes simplex virus, tumor


Neurofibromatosis type 2 (NF2) is an autosomal dominantly inherited genetic disorder characterized by neoplastic and dysplastic lesions of Schwann cells (schwannomas and schwannosis), meningeal cells (meningiomas and meningioangiomatosis), and glial cells (gliomas and glial microhamartomas) [1]. Patients often develop multiple schwannomas, spinal cord schwannomas, and/or cutaneous schwannomas in the periphery, and meningiomas and astrocytomas/ependymomas in the brain [2–4]. In this condition, usually germ line mutations of one allele of this gene [5] combined with somatic mutations of the other allele lead to functional loss of the encoded protein, termed merlin [6] or schwannomin [5], with consequent loss of growth regulation of some cells, e.g., Schwann cells. Most of the germ line and somatic mutations in the NF2 gene result in either a stop codon, a splicing alteration, or a frameshift, leading to the production of a truncated protein [7,8]. In addition, in-frame deletions and missense mutations have also been found, suggesting that mutation of particular functional domains can also abolish the function of the NF2 protein. Inactivation of the NF2 protein product occurs in both sporadic and familial schwannomas and meningiomas, supporting the NF2 gene as a tumor suppressor gene [9–13].

The NF2 protein is a member of the ezrin, radixin, moesin (ERM) family of cytoskeleton/membrane linker proteins [5,6]. Endogenous merlin is localized to the plasma membrane of Schwann and other cell types [14]. When transiently expressed in various cell types, some mutant NF2 proteins corresponding to naturally occurring human mutations demonstrate abnormal cellular localization [15,16]. For example, whereas carboxy terminal deletion mutants remain localized at cell membrane, mutants with intact carboxy terminal but deleted or altered amino terminal domains relocalize to the perinuclear cytoplasmic region. Relocalization to the cytoplasm was also observed for a mutant protein modeled from naturally occurring human NF2 mutation in which exons 2 to 3 are spliced out without a frameshift Sch-Δ(39–121) [17].

Schwannoma and meningioma tumors form in NF2 patients by overgrowth of cells, which support neurons in the nervous system. Although rarely becoming malignant, schwannomas and meningiomas associated with NF2 can severely compromise neural function leading to paralysis, deafness, and death through compression of critical brain nerves and structures [18] or blockade of cerebrospinal fluid (CSF) flow [19]. In NF2, the most severe and life-threatening tumors are usually those at the skull base. They may be cranial nerve schwannomas (e.g., some vestibular schwannomas are inoperable) or skull base meningiomas, which, due to their size or multiplicity, are not surgically accessible. In fact, the cause of death of many NF2 patients is progressive brainstem compression from such tumors, and death occurs, on average, 15 years after diagnosis of such lesions [20]. Other clinical problems in need of new therapeutic intervention are multiple meningiomas and spinal cord tumors. Repeated resection of tumor material can be performed, but after several craniotomies, the patients are left so debilitated that further surgery is not helpful.

These types of tumors are appropriate targets for gene therapy in its present state of development, as they grow slowly, remain localized to focal areas of the body, and can be readily pinpointed with magnetic resonance imaging (MRI). The humane advantages of this type of therapy are that it is carried out by direct injection of tumor masses, and that the vectors, transgene products, and prodrugs have essentially no toxicity to normal tissue, and hence should have minimal morbidity to patients. The overall goal of our project involves directing and evaluating gene delivery to these types of tumors in animal models using minimally invasive imaging methods and vectors applicable to future human use.

Although still in its infancy, gene therapy has the potential to serve as an adjunct to current therapies. For treatment of benign tumors, a number of therapeutic transgenes can be employed, such as those encoding prodrug activation enzymes demonstrated to arrest growth and reduce volume [21,22]. Two important components to the development of this promising technology are: 1) animal models that form spontaneous tumors of the same genetic etiology and same cellular type as found in humans; and 2) imaging modalities that will allow detection of lesions and monitoring of gene delivery and therapeutic efficacy in living animals. The strategic advantage of NF2, in this regard, is that a mouse model exists, which parallels the human condition, and the lesions are usually focal and can be readily pinpointed with MRI, which allows direct targeted injection of tumor masses. MRI is able to noninvasively provide information regarding tumor metabolism and pathophysiology. Because MRI can provide information about in vivo tumor metabolism and pathophysiology nondestructively, preclinical results from animal models may be applied in clinical settings [23]. Based on extensive experimental/preclinical and clinical studies of gene therapy for gliomas [24–28], NF2 lesions, due to their benign and focal nature, appear to be a realistic target for gene therapy.

In this study, we have used a transgenic murine model for NF2, which employs heterozygous mice expressing the mutant Sch-Δ(39–121) (line 27) NF2 protein, similar to that found in some NF2 patients, in Schwann cells under the P0 promoter [29]. The mutated transgene consists of an interstitial deletion of amino acids 39 to 121 in the aminoterminal domain of human NF2 cDNA. Previous pathologic analyses of these transgenic mice have demonstrated a high incidence of Schwann cell-derived tumors and Schwann cell hyperplasia in older animals at the time of sacrifice. In particular, the average age of tumor incidence in these P0-Sch-Δ(39–121) transgenic mice was 17.5 months. Macroscopic tumors were found in the uterus of 8 of 20 female transgenic mice between the age of 13 and 20.5 months, whereas microscopic foci of Schwann cell proliferation (schwannosis) were detected in muscle and spinal ganglia as early as 6 and 9 months, respectively [29].

The aims of this particular study were to determine if schwannomas found in these transgenic mice could be detected with MRI, and to evaluate whether these schwannomas were infectable with herpes simplex virus (HSV) viral vectors. The HSV virion is one of the most efficient gene transfer vehicles for central nervous system-derived cells, such as brain tumors [30]. We have detected schwannomas in these mice using MRI and correlated this with histochemical and immunocytochemical analysis. We have also demonstrated infectability in these schwannomas with recombination HSV vectors as a platform for therapeutic gene delivery.

Materials and Methods


Fourteen transgenic mice (11 males and 3 females), ages 13 to 20 months, were used for this study. These [P0-Sch-Δ(39–121)] transgenic mice express a mutant form of merlin with an in-frame interstitial deletion in the amino terminal domain of NF2 under the P0 promoter [29]. Mice were genotyped by isolating tail DNA using the DNeasy Tissue Kit (Cat no. 69506; Qiagen, Valencia, CA). PCR was performed on the purified tail DNA using the forward primer GAP 3.3: 5′-AGATACTGACATGAAGCGG-3′ and the reverse primer TAG antisense: 5′-TTACTTGCCCAGCCGGTTCAT-3′. A 320-bp fragment represents the mutant NF2 transgene and no band is detected in wild-type FVBN mice (WT). A 320-bp band was found in all transgenic animals when PCR was performed with these primers and tail DNA, whereas no band is present in this PCR reaction with tail DNA from a nontransgenic wild-type mouse.

To detect transgene-specific expression, the mutant protein was tagged with a vesicular stomatitis virus (VSV) glycoprotein G epitope [29,31]. The 11 carboxy-terminal amino acids from the VSV-G, preceded by a proline-rich secondary structure breaker (GPPGP), were linked in-frame to the carboxyl terminus of the deletion mutant. The mutated fusion protein can be detected with antibodies raised against the tag corresponding to the carboxy-terminal end of the glycoprotein G (see Immunostaining section below for specifics on the VSV-G antibody).


MRI was employed to localize spontaneous schwannoma tumors. Imaging was performed using a 1.5-T clinical imaging system (System 5X; General Medical Systems, Milwaukee, WI) using a 3-in. surface coil. Anesthesized animals were taped to a Plexiglass plate, and were positioned immediately below the surface coil. Imaging sequences included conventional T1-weighted sequences (TR/TR: 300/11 milliseconds) with and without fat suppression and T2-weighted turbo spin echo sequence (TR/TE 3000/100 milliseconds) with and without fat suppression. The field of view was 8 cm, the slice thickness 1.5 mm, and the imaging matrix was 512x192, yielding a voxel dimension of 156x416x1500 µm. It was anticipated that peripheral nerve Schwann cell hyperplasias and schwannomas would appear hyperintense on T2-weighted sequences. For this reason, an initial study was performed to optimize the type of T2-weighted sequence (spin echo versus fast spin echo versus gradient echo). All animals received an intravenous injection of contrast agent gadolinium (Gd)-DTPA and dynamic imaging was performed for enhanced detection of lesions. To correlate the MRI with the presence and size of tumors, necropsy and careful correlative histology were performed.


Those animals that had tumors, as diagnosed by MRI, were sacrificed by exposure to CO2 and underwent necropsy. Tumors were removed from animals and placed in 10% formalin in phosphate-buffered saline (PBS) for 24 hours prior to being dehydrated in graded solutions of alcohol and xylene and embedded in paraffin [32]. After embedding, 6-µm sections were cut with a Jung Histocat microtome (Leica, Nussloch, Germany), and mounted on charged and precleaned Fisher Biotech Probe on Plus Microscope slides (Fisher Scientific, Pittsburgh, PA). Slides were incubated at 65°C for 1 hour. For hematoxylin and eosin (H&E) staining, tissue sections on slides were deparaffinized in xylene for 10 minutes, hydrated in a series of ethanol solutions (100%, 90%, 70%) for 3 minutes each, rinsed in PBS for 2 minutes, stained with hematoxylin for 2 minutes, and then rinsed in distilled water until excess stain was removed. Tissue sections were then dipped in an eosin solution two to three times, and rinsed in distilled water until excess stain was removed. Tissue sections were dehydrated in a series of ethanol solutions (70%, 90%, 100%) for 3 minutes each, and then incubated in xylene for 1 minute prior to being coverslipped with Permount.


For immunostaining of tissue sections, tissue was deparaffinized and hydrated by being incubated in xylene for 15 minutes, 100% ethanol for 3 minutes, 95% ethanol for 3 minutes, 75% ethanol for 3 minutes, 50% ethanol for 3 minutes, and then rinsed in PBS twice for 3 minutes each. Tissue sections were then permeabilized in 0.5% Triton X in PBS for 10 minutes, and treated with blocking buffer (5% goat serum in 1% BSA diluted in 1x PBS) for 30 minutes. Two polyclonal primary antibodies, rabbit anti-cow S100 (Dako, Glostrup, Denmark) and anti-VSV-G tag (Medical and Biological Laboratories, Naka-ku, Nagoya, Japan) were diluted 1:200 in blocking buffer (5% goat serum in 1% BSA diluted in 1x PBS) and then applied to tissue sections for 1 hour at 37°C. Following the primary antibody incubation, tissue was washed four to six times with blocking buffer. For the S-100 protein staining, the secondary antibody goat anti-rabbit IgG-Cy3 (Jackson Immuno Research Laboratories, West Grove, PA) was applied to tissue at a dilution of 1:200 for 30 minutes at room temperature. For VSV-G staining, the secondary antibody goat anti-rabbit IgG-FITC (Biosource International, Camarillo, CA) was applied to tissue at a dilution of 1:200 for 30 minutes at room temperature. Following incubation in the secondary antibody, tissues were rinsed four to six times in 1% BSA and mounted with glass coverslips and fluorescent mounting medium (cat no. S3023; Dako), prior to being viewed with an Olympus microscope.

Infection with HSV

The replication-conditional HSV vector, hrR3, has a deletion in the gene for ribonucleotide reductase (ICP6) replaced with lacZ, thereby placing the lacZ under an early viral promoter [33]. Tumors were injected with hrR3 (2.3x108 pfu in 30 µl) and, 3 days later, removed from the animal, fixed for 24 hours in 4% paraformaldehyde, then placed in 25% sucrose for several days. Tissue was then frozen, cut into 40-µm sections, and analyzed by histology for β-galactosidase expression by staining the sections with X-gal buffer [1 mg/ml 5-bromo-4-chloro-3-indoxyl β-galactosidase, 5 mM K3Fe(CN)6, 5 mM K3Fe(CN)6 2 mM MgCl2 in 0.1 M sodium phosphate buffer (pH 7.4)] at 37°C for 12 hours [34].


Detection of Schwannomas in NF2 Transgenic Mice by MRI

Previous studies had shown that NF2 transgenic [P0-Sch-Δ(39–121)] animals typically demonstrate Schwann cell hyperplasias and/or schwannomas in 80% of animals by 9 months of age, especially in the spinal ganglia and around peripheral nerve endings in skeletal muscle [29]. In this study, MRI was conducted on 14 transgenic mice, 13 to 20 months of age, over a 9-month period. Eighty-six percent (12/14) of these mice showed tumors by imaging. Specifically, 21% of the mice showed tumors in the intercostal muscles, 14% in the limb muscles, 7% in the spinal cord and spinal ganglia, 7% in the external ear, 14% in the muscle of the abdominal region, and 7% in the intestines; 66% (2/3) of the female mice had uterine tumors (Table 1). Multiple tumors were detected by MRI in 21% of mice; for instance, one male mouse had tumors in the skeletal muscles of both the limb and rib.

Table 1
Distribution of Tumors as Detected by MRI.

In general, the tumors demonstrated marked hyperintensity using the T2W1 fat saturation sequence, were isointense or hypointense with other organs using the T1W1 spin sequence, showed significant enhancement following intravenous contrast administration, and were well defined with a sharp margin. These imaging characteristics are similar to those observed in schwannomas in human patients [35–38]. Tumors measured between 3 and 7 mm in length. All tumors identified by necropsy were also detected by MRI. However, prospective reading of MRI scans suggested equivocal findings not confirmed by histology in 7% mice imaged. Most of these findings were related to volume averaging artifacts. In 7% of mice that were thought to have tumors by imaging, no tumors were found by necropsy and histological examination.

Figure 1 illustrates MRI of a male mouse (age 18 months) that had tumors in the muscles of the right forelimb (Panels A–C) and in the intercostal muscles (Panels D–F). Two of three female mice imaged by MRI had uterine tumors (Figure 2). Using T1W1 imaging, the tumor displayed isointensity with other organs (Figure 2A). Using the T2W1 fat saturation sequence, the uterine tumor had marked hyperintensity (Figure 2B–D) and was well defined with a sharp margin, imaging characteristics similar to those observed for schwannomas in human patients [35–38]. An intestinal tumor in one female mouse was also evident.

Figure 1
MRI of multiple intramuscular tumor s in a NF2 dominant mutant transgenic mouse. An anesthesized transgenic male mouse (age 18 months) was taped to a Plexiglass plate, which was positioned immediately below a 3-in surface coil. MRI detected a lesion in ...
Figure 2
Histopathology and immunostaining for the Schwann cell marker S-100 protein of the tumor from the same mouse, which was imaged by MRI as shown in Figure 2. H&E staining was performed on paraffin-embedded sections. The tumor was dispersed among ...

Each mouse underwent MRI at least once, and several mice were imaged up to three times. If the diagnosis of tumor from MRI was clear-cut, the mice were sacrificed for a necropsy and histological examination. Whereas the mice examined in this study were not followed to document tumor growth over time, future studies will address volumetric changes of these schwannomas over time and the response of these tumors to therapeutic treatment.

Characterization of Schwannomas in NF2 Transgenic Mice

Immunohistochemical studies were performed on sections of tumors from those transgenic mice that had tumors indicated by MRI and histological analysis. The Schwann cell origin of these tumors was examined by staining with an antibody to S-100 protein, which is a marker for cells of Schwann cell origin. Immunohistochemistry was performed using a polyclonal antibody to S-100 protein (Dako, Carpinteria, CA) on tumor sections from the right forelimb of the mouse, which was imaged by MRI (Figure 1) and on sections from the forelimb of a normal mouse. Positive immunostaining was present in paraffin sections from the intramuscular tumor (Figure 3D), but absent in sections of normal skeletal leg muscle (Figure 3E) and absent when incubated with secondary antibody alone (Figure 3F), suggesting that this intramuscular tumor is a schwannoma. Likewise, the uterine tumor illustrated in Figures 4–6 also stains positively for S-100 protein. These data indicate that the tumors detected by MRI and histology in the NF2 transgenic mice P0-Sch-Δ(39–121) are schwannomas. Other immunohistochemical studies confirm that the tumor sections are positive for VSV-G, the tag for the mutated human NF2 transgene (Figure 7). Preliminary experiments involving histological staining indicate that these schwannomas do not stain for myelin (data not shown), consistent with previous evidence of disaggregation of myelin sheaths in vestibular human schwannomas [39].

Figure 3
MRI of a uterine tumor in a NF2 dominant mutant transgenic mouse [P0-Sch-Δ(39–121)]. MRI detected a large uterine tumor with a well-defined margin, which showed isointensity on T1-weighted image (A) and hyperintensity on fat-saturated ...
Figure 7
Detection of VSV-G marker for mutated NF2 gene in schwannomas from NF2 transgenic mice. Paraffin sections from the tumors are illustrated in Figure 7, extracted from the mouse shown in Figure 6, and were immunostained with a polyclonal antibody to VSV-G. ...

Infectability of Schwannomas with a Replication-Conditional HSV Vector

We have also investigated the infectability of these schwannomas, both in cell culture and in vivo, with the replication-conditional HSV vector, hrR3, which is capable of replication only in dividing cells, thereby killing them [26]. Because most cells in the adult nervous system are nondividing, this cytotoxicity is selective for tumor cells. hrR3 contains the reporter gene lacZ [33] that facilitates tracking of vector-infected cells.

Experiments suggest that the schwannomas are highly infectable with hrR3, both in vivo and in cell culture. For in vivo studies, we waited for 3 to 5 days following infection of hrR3 into the tumor to stain for β-galactosidase expression to allow the virus to replicate in dividing cells. In this study, we did not try to quantitate the size of tumors infected with hrR3 because they were diffuse in shape and volumetric analysis was difficult. The tumors were chosen for infection based on their location, as they were palpable and externally visible, allowing for targeted injection.

Figure 8 illustrates β-galactosidase expression in tumor tissue infected with hrR3 3 days following infection (Figure 8A), compared to the lack of β-galactosidase expression in tumor tissue, which was not injected with hrR3 (Figure 8B). In order to determine if the cells infected with hrR3 were schwannomas, double staining of tumors infected with hrR3 was also carried out with X-gal staining and immunocytochemistry using an antibody to S-100 protein. Figure 8C and D illustrates that b-galactosidase expression and S-100 protein staining share a similar pattern of distribution in tumor tissue infected with hrR3, suggesting that the schwannoma cells themselves are infectable with hrR3. In culture, schwannoma tumor cells infected with hrR3 at an MOI of 0.5 to 2.0 and fixed 48 hours later stained positively for β-galactosidase expression, and preliminary evaluation indicated that the extent of β-galactosidase expression was proportional to the amount of virus added (data not shown).

Figure 8
β-Galactosidase expression and S-100 protein staining share a similar pattern of distribution in tumor tissue infected with hrR3 (2.3 x 108 pfu). Three days after injection of virus into the tumor, tumor tissue was removed from the animal, fixed ...


Our findings demonstrate that MRI can be used to detect schwannomas in a transgenic murine model for human NF2. Histology and immunohistochemistry have confirmed the Schwann cell origin of these tumors, and expression of the marker, VSV-G, demonstrates the role of the mutated NF2 transgene in their oncogenesis. The ability to detect these schwannomas in living animals in a murine model with MRI, a noninvasive technique, will allow targeting of spontaneous tumors for treatment. MRI should enable monitoring of volumetric changes of schwannomas in response to therapeutic interventions, although for some tumors, determination of tumor volume will be difficult due to their locations and complex tumor geometry. This opens the way to future studies in which therapeutic intervention can be tested in this transgenic murine model of NF2 as preclinical assessment of the potential for clinical application.

Importantly, we have shown in this transgenic murine model of NF2 that spontaneous schwannomas are highly infectable with HSV vectors, which can serve as a platform for therapeutic interventions. The vector tested in this study is a replication-conditional virus bearing the viral thymidine kinase (tk) gene, which has already been shown to have therapeutic efficacy in mouse models of gliomas [26] and has formed the basis of a phase I clinical trial in human glioblastoma patients [40]. hrR3 has a mutated ribonucleotide reductase gene, so that this vector replicates selectively in dividing cells with high levels of endogenous ribonucleotide reductase, such as tumor cells [41]. hrR3 also encodes the HSV-tk gene, which can convert the prodrug, ganciclovir, into a nucleoside analogue that is toxic to dividing cells, resulting in selective generation of a chemotherapeutic drug in the tumor. Thus, addition of ganciclovir to hrR3-infected cells can enhance the ability of hrR3 to destroy tumor cells [25,26]. Although it is not known if the replication rate of these schwannomas will support virus propagation or tk/ganciclovir killing, still the HSV vectors can serve to deliver therapeutic genes to these tumors.

We will be evaluating the therapeutic efficacy of HSV recombinant hrR3 vectors combined with ganciclovir administration in schwannoma models by evaluation of tumor volume over time and of tumor-selective viral replication by histochemistry of the lacZ reporter. The humane advantages of this type of gene therapy are that it is carried out by direct injection of tumor masses rather than invasive surgery, and that vectors, transgene products, and prodrugs have essentially no toxicity to normal tissue, and hence, they should have minimal morbidity to patients. If these vectors prove effective in reducing schwannoma volume, this treatment could replace current surgical interventions, which frequently result in damage to critical nerve functions.


1This work was funded by the Department of the Army, US Army Research Medical Research and Material Command, Award no. DAMD17-00-1-0537; the MGH Fund for Medical Discovery awarded to S.M.M.; the Center Grant (P50-CA86355); and the Small Animal Imaging Grant (R24-CA92782) awarded to R.W.

aDrs. Messerli and Tang contributed equally to this work.


1. Louis DN, Stemmer-Rachamimov AO, Wiestler OD. Neurofibromatosis type 2. World Health Organization Classification of Tumours. In: Kleihues P, Cavenee WK, editors. Pathology and Genetics, Tumours of the Nervous System. Lyon, France: IARC Press; 2000. pp. 219–222.
2. Eldridge R. Central neurofibromatosis with bilateral acoustic neuroma. Adv Neurol. 1981;29:57–65. [PubMed]
3. Mautner VF, Lindenau M, Baser M, Hazim W, Tatagiba M, Haase JW, Samii M, Wais R, Pulst SM. The neuroimaging and clinical spectrum of neurofibromatosis type 2. Neurosurgery. 1996;40:880–886. [PubMed]
4. Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450–461. [PubMed]
5. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman C, Plougastel B. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature. 1993;363:515–521. [PubMed]
6. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, Haase VH, Ambrose CM, Munroe D, Bove C, Haines JL, Martuza RL, MacDonald ME, Seizinger BR, Short MP, Buckler AJ, Gusella JF. A novel moesin-ezrin-radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791–800. [PubMed]
7. De Vitis LR, Tedde A, Vitelli F, Ammannati F, Mennonna P, Bigozzi U, Montali E, Papi L. Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic meningiomas. Hum Genet. 1996;97:632–637. [PubMed]
8. MacCollin M, Ramesh V, Jacoby LB, Louis DN, Rubio MP, Pulaski K, Trofatter JA, Short MP, Bove C, Eldridge R. Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet. 1994;55:314–320. [PMC free article] [PubMed]
9. Bianchi AB, Hara T, Ramesh V, Gao J, Szanto-Klein AJ, Morin F, Menon AG, Trofatter JA, Gusella JF, Seizinger BR, Kley N. Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumor types. Nat Genet. 1994;6:185–192. [PubMed]
10. Bijlsma EK, Merel P, Bosch DA, Westerveld A, Delattre O, Thomas G, Hulsebos TJ. Analysis of mutations on the SCH gene in schwannomas. Genes Chromosomes Cancer. 1994;11:7–14. [PubMed]
11. Jacoby LB, MacCollin M, Barone R, Ramesh V, Gusella JF. Frequency and distribution of NF2 mutations in schwannomas. Genes Chromosomes Cancer. 1996;17:45–55. [PubMed]
12. Sainz J, Huynh DP, Figueroa K, Ragge NK, Baser ME, Pulst SM. Mutations of the neurofibromatosis type 2 gene and lack of the gene product in vestibular schwannomas. Hum Mol Genet. 1994;3:85–91. [PubMed]
13. Twist EC, Ruttledge MH, Rousseau M, Sanson M, Papi L, Merel P, Delattre O, Thomas G, Rouleau GA. The neurofibromatosis type 2 gene is inactivated in schwannomas. Hum Mol Genet. 1994;3:147–151. [PubMed]
14. MacCollin M, Gusella JD. Molecular biology. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 3rd ed. Baltimore: John Hopkins Univ. Press; 1999. pp. 351–359.
15. Shaw RJ, McClatchey AI, Jacks T. Localization and functional domains of the neurofibromatosis type II tumor suppressor, merlin. Cell Growth Differ. 1998;9:287–296. [PubMed]
16. Xu L, Gonzalez-Agnosti C, Beauchamp R, Pinney D, Sterner C, Ramesh V. Analysis of molecular domains of epitope-tagged merlin isoforms in Cos-7 cells and primary rat Schwann cells. Exp Cell Res. 1998;238:231–240. [PubMed]
17. Deguen B, Merel P, Goutebroze L, Giovannini M, Reggio H, Arpin M, Thomas G. Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton membrane. Hum Mol Genet. 1998;7:217–226. [PubMed]
18. Short MP, Richardson EPJ, Haines JL, Kwiatkowski DJ. Clinical, neuropathological and genetic aspects of the tuberous sclerosis complex. Brain Pathol. 1995;5:173–179. [PubMed]
19. Renowden SA, Anslow P. The effective use of magnetic resonance imaging in the diagnosis of acoustic neuromas. Clin Radiol. 1993;48:25–28. [PubMed]
20. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84:603–618. [PubMed]
21. Lam YP, Breakefield XO. Potential of gene therapy for brain tumors. Hum Mol Genet. 2001;10:777–787. [PubMed]
22. Jane JA, Helm GA. Gene therapy for skull base tumors. Neurosurg Clin N Am. 2000;11:703–716. [PubMed]
23. Evelhoch JL, Gillies RJ, Karczmar GS, Koutcher JA, Maxwell RJ, Nalcioglu O, Raghunand N, Ronen SM, Ross BD, Swartz HM. Applications of magnetic resonance in model systems: cancer therapeutics. Neoplasia. 2000;2:152–165. [PMC free article] [PubMed]
24. Kramm CM, Chase M, Herrlinger U, Jacobs A, Pechan PA, Rainov NG, Sena-Esteves M, Aghi M, Barnett FH, Chiocca EA, Breakefield XO. Therapeutic efficacy and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy. Hum Gene Ther. 1997;20:2057–2068. [PubMed]
25. Kramm CM, Rainov NG, Sena-Esteves M, Barnett FH, Chase M, Herrlinger U, Pechan PA, Chiocca EA, Breakefield XO. Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment. Hum Gene Ther. 1996;7:1989–1994. [PubMed]
26. Boviatsis EJ, Parks S, Sena-Esteves M, Kramme C, Chase M, Efird JT, Wei M, Breakefield XO, Chiocca EA. Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res. 1994;54:5745–5751. [PubMed]
27. Alavi JB, Eck SL. Gene therapy for high grade gliomas. Expert Opin Biol Ther. 2001;1:239–252. [PubMed]
28. Kruse CA, Lamb C, Hogan S, Smiley WR, Kleinschmidt-Demasters BK, Burrows FJ. Purified herpes simplex thymidine kinase retroviral particles. Influence of clinical parameters and bystander killing mechanisms. Cancer Gene Ther. 2000;7:118–127. [PubMed]
29. Giovannini M, Robanus-Maandag E, Niwa-Kawakita M, van der Walk M, Woodruff JM, Goutebroze L, Merel P, Berns A, Thomas G. Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein. Genes Dev. 1999;15:978–986. [PMC free article] [PubMed]
30. Jacobs A, Breakefield XO, Fraefel C. HSV-1 based vectors for gene therapy of neurological diseases and brain tumors: Part I. HSV-1 structure, replication, and pathogenesis. Neoplasia. 1999;1:387–401. [PMC free article] [PubMed]
31. Kreis TE. Microinjected antibodies against the cytoplasmic domain of vesicular stomatitis virus glycoprotein block its transport to the cell surface. EMBO J. 1986;5:931–941. [PMC free article] [PubMed]
32. McClatchey AI, Saotome I, Mercer K, Crower D, Gusella JF, Bronson RT, Jacks T. Mice heterozygous for a mutation at the NF2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998;12:1121–1133. [PMC free article] [PubMed]
33. Goldstein DJ, Weller SK. Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis; isolation and characterization of an ICP6 lacZ insertion mutant. J Virol. 1988;62:196–205. [PMC free article] [PubMed]
34. Price J, Turner D, Cepko C. Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer. Proc Natl Acad Sci USA. 1987;84:156–160. [PMC free article] [PubMed]
35. Abe T, Kawamura N, Homma H, Sasaki K, Izumiyama H, Matsumoto K. MRI of orbital schwannomas. Neuroradiology. 2000;42:466–468. [PubMed]
36. Hayasaka K, Tanaka Y, Soeda S, Huppert P, Claussen CD. MR findings in primary retroperitoneal schwannomas. Acta Radiol. 1999;40:78–82. [PubMed]
37. Hayashi M, Kubo O, Sato H, Taira T, Tajika Y, Izawa M, Takakura K. Correlation between MR image characteristics and histological features of acoustic schwannoma. Noshuyo Byori. 1996;13:139–144. [PubMed]
38. Soderlund V, Goranson H, Bauer HC. MR imaging of benign peripheral nerve sheath tumors. Acta Radiol. 1994;35:282–286. [PubMed]
39. Sans A, Brarolami S, Fraysse B. Histopathology of the peripheral vestibular system in small vestibular schwannomas. Am J Otol. 1996;17:324–326. [PubMed]
40. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Plamer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–874. [PubMed]
41. Yoon SS, Carroll NM, Chiocca EA, Tanabe KK. Cancer gene therapy using a replication-competent herpes simplex virus type 1 vector. Ann Surg. 1998;228:366–374. [PMC free article] [PubMed]

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