The early region of human papovavirus JC induces dysmyelination in transgenic mice

Small, J A; Scangos, George; Cork, Linda C.; Jay, Gilbert; Khoury, George

doi:10.1016/0092-8674(86)90855-x

Cited by 140 publications

(66 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The founder mice containing the JCV sequences and nearly 50% of their transgenic ospring (35 of 79 counted) showed signs of illness at 9 ± 13 months or more of age manifested by poor grooming, paralysis of rear limbs, and hunched posture. None of the ospring exhibited shaking with motion or shivering, a phenotype which was observed in a JCV(Mad) transgenic line and was caused by dysmyelination in the CNS (Small et al, 1986a). Analysis of DNA from the aected animals by PCR and direct sequencing revealed the integrity of the transgene with no evidence for the rearrangement of the JCV(CY) control sequence in the transgenic animals ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

et al. 1999

View full text Add to dashboard Cite

JCV is a papovavirus which is widespread in the human population. The prototype Mad-1 variant of JCV induces a fatal demyelinating disease of the central nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-1) to the CNS is attributed to the tissue-speci®c regulation of the viral early promoter which is responsible for the production of the viral regulatory protein, T-antigen. The archetype form of this virus, JCV(CY), which has been repeatedly isolated from the urine of PML and non-PML individuals, is distinct from JCV(Mad-1) in the structural organization of the regulatory sequence. To characterize the tissue speci®c expression of JCV(CY) and to investigate its potential in inducing disease, transgenic mice containing the early region of JCV(CY) were generated. Some of these mice between 9 ± 13 months of age exhibited signs of illness as manifested by paralysis of rear limbs, hunched posture, and poor grooming. Neuropathological examination indicated no sign of hypomyelination of the brain, but surprisingly, revealed the presence of primitive tumors originating from the cerebellum and the surrounding brain stem. The tumor masses also in®ltrated the surrounding tissue. Results from RNA and protein studies revealed a high level of Tantigen mRNA expression in hindbrains of clinically normal and aected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of JCV(CY) induced tumor in transgenic mice to the human medulloblastoma/primitive neuroectodermal tumor (PNETs) in location, histologic appearance, and expression of marker proteins strongly suggests the utility of this novel animal model for the study of human brain tumors.

show abstract

Section: Resultsmentioning

confidence: 99%

Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Two mice of the LTR/env-1 line exhibited an easily detectable lower limb weakness, which was confirmed pathologically. However, under a more detailed neurological examination, 17 mice (6%) of the LTR/env Tg lines and 5 (6%) mice of the LTR/NI-neuro Tg line 24 exhibited an adduction reflex of the lower limbs when held by the tail (Table 1), a sign characteristic of mice inoculated with Cas-Br-E MuLV.…”

mentioning

confidence: 99%

Neurological disease induced in transgenic mice expressing the env gene of the Cas-Br-E murine retrovirus.

Kay¹,

Gravel²,

Pothier³

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The Cas-Br-E murine leukemia virus induces a spongiform myeloencephalopathy in susceptible mice. We constructed transgenic mice harboring either the viral genome (in a replication-defective form) or only its env gene. Low levels of expression of either transgene resulted in mild neuropathology and/or signs of neurological disease in more than half of these mice. These results indicate that the disease can occur in the absence of virus replication and strongly suggest that the env gp7O/pl5E complex is sufficient to induce disease.The Cas-Br-E murine leukemia virus (MuLV) induces a lower motor neuron disease in susceptible mice (reviewed in refs. 1 and 2), resulting in vacuolization, neuronal loss and intense gliosis within the grey matter, and gliosis with some demyelination in the white matter. These are found predominantly in the brainstem and in the anterior horn of the spinal cord (3, 4). Three determinants of neuropathogenicity have been identified on this viral genome. The most important has been mapped within the env gp7O sequences and is responsible for the induction of the specific spongiform lesions (5-7). The other determinants, localized within the long terminal repeat (LTR) or the R-U5-5' leader sequences, influence the incidence, severity, and the central nervous system (CNS) location of the lesions (8,9) or the latency of the disease (7, 10), respectively. However, the mechanism by which the Cas-Br-E MuLV causes spongiform lesions remains unknown. Since the gp7O harbors an important determinant of pathogenicity, we have proposed that the disease is receptormediated (2, 5, 6). To better understand the pathogenesis of this disease, we constructed transgenic (Tg) mice carrying either the coding viral sequences of Cas-Br-E MuLV or only its env sequences, both under the transcriptional control of MuLV LTR. MATERIALS AND METHODSPreparation of DNA for MicroiDJection. The transgenes were constructed essentially as before (11), using the clone pNE-8 of Cas-Br-E MuLV (12) (Fig. 1).Construction of Tg Mice. Tg mice were generated essentially as described before using one cell (C57BL/6 x C3H)F2 embryos for microinjection (11,13). The (C57BL/6 x C3H)F1, CD-1, CFW/D, and C3H mice were purchased from Charles River Breeding Laboratories. Southern hybridization analysis of tail DNA was performed with a 32P-labeled Taq I-BamHI Cas-Br-E MuLV env-specific DNA probe (14). Positive mice were first bred to C3H and then to CFW/D outbred mice. Breeding to CFW/D was carried out because this strain was found to be susceptible to 15). For assessment of neuropathology, Tg mice were bred into C3H mice for one to three generations and subsequently into CFW/D mice for zero to three generations. For the evaluation of balance and muscle strength, Tg mice were crossed into C3H mice for three to six generations and subsequently into CFW/D mice for one to three generations. Control mice, housed in the same room, were age-matched CFW/D, (C57BL/6 x C3H)F1, C3H, and non-Tg littermates.Detection of Transgene Expression. In situ hyb...

show abstract

“…Ten founder animals contained the transgene, as determined by PCR analysis of genomic DNA extracted from the tail. Of the 10 mice, one exhibited shaking of the tail suggestive of a dysmyelination phenotype described earlier (Small et al, 1986a). This animal died at two months of age before being successfully mated.…”

Section: Resultsmentioning

confidence: 99%

“…While initial descriptions of JCV T-antigen transgenic mice reported a dysmyelinating phenotype (Small et al, 1986a), simultaneous experiments by the same group were the ®rst to report primitive neuroectodermal origin tumors induced by the same transgene (Small et al, 1986b). The ability of JCV T-antigen to induce two distinct phenotypes has been attributed in part to expression of the JCV oncoprotein in the absence of viral lytic infection.…”

Section: Discussionmentioning

confidence: 99%

Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice

et al. 2000

View full text Add to dashboard Cite

The early region of human papovavirus JC induces dysmyelination in transgenic mice

Cited by 140 publications

References 20 publications

Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

Neurological disease induced in transgenic mice expressing the env gene of the Cas-Br-E murine retrovirus.

Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice

Contact Info

Product

Resources

About