Off-Target Effects in Transgenic Mice: Characterization of Dopamine Transporter (DAT)-Cre Transgenic Mouse Lines Exposes Multiple Non-Dopaminergic Neuronal Clusters Available for Selective Targeting within Limbic Neurocircuitry

Abstract Although NPM1 gene mutations leading to aberrant cytoplasmic expression of nucleophosmin (NPMc+) are the most frequent genetic lesions in acute myeloid leukemia, there is yet no experimental model demonstrating their oncogenicity in vivo. We report the generation and characterization of a transgenic mouse model expressing the most frequent human NPMc+ mutation driven by the myeloid-specific human MRP8 promoter (hMRP8-NPMc+). In parallel, we generated a similar wild-type NPM trans-genic model (hMRP8-NPM). Interestingly, hMRP8-NPMc+ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic littermates and hMRP8-NPM transgenic mice remained disease free. These findings provide the first in vivo evidence indicating that NPMc+ confers a proliferative advantage in the myeloid lineage. No spontaneous acute myeloid leukemia was found in hMPR8-NPMc+ or hMRP8-NPM mice. This model will also aid in the development of therapeutic regimens that specifically target NPMc+.

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Human Desmoglein-2 and Human CD46 Mediate Human Adenovirus Type 55 Infection, but Human Desmoglein-2 Plays the Major Roles

Journal of Virology ◽

10.1128/jvi.00747-20 ◽

2020 ◽

Vol 94 (17) ◽

Author(s):

Ying Feng ◽

Changhua Yi ◽

Xinglong Liu ◽

Linbing Qu ◽

Wan Su ◽

...

Keyword(s):

Transgenic Mice ◽

Transgenic Mouse ◽

Gene Knockout ◽

Human Adenovirus ◽

Adenovirus Type ◽

Host Cells ◽

Respiratory Pathogen ◽

Cellular Receptors ◽

Fiber Protein ◽

Mouse Lines

ABSTRACT Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. In this study, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Nonpermissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although nontransgenic mice were resistant to HAdV55 infection, infection with HAdV55 was significantly increased in hDSG2+/+ mice but was much less increased in hCD46+/+ mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics. IMPORTANCE Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immunocompetent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than for hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise nontransgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.

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Characterization of three different transgenic mouse lines that carry human poliovirus receptor gene?influence of the transgene expression on pathogenesis

Archives of Virology ◽

10.1007/bf01310797 ◽

1994 ◽

Vol 139 (3-4) ◽

pp. 351-363 ◽

Cited By ~ 38

Author(s):

S. Koike ◽

C. Taya ◽

J. Aoki ◽

Y. Matsuda ◽

I. Ise ◽

...

Keyword(s):

Transgenic Mouse ◽

Transgene Expression ◽

Receptor Gene ◽

Poliovirus Receptor ◽

Mouse Lines

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Transmission and characterization of bovine spongiform encephalopathy sources in two ovine transgenic mouse lines (TgOvPrP4 and TgOvPrP59)

Journal of General Virology ◽

10.1099/vir.0.82062-0 ◽

2006 ◽

Vol 87 (12) ◽

pp. 3763-3771 ◽

Cited By ~ 27

Author(s):

C. Cordier ◽

A. Bencsik ◽

S. Philippe ◽

D. Bétemps ◽

F. Ronzon ◽

...

Keyword(s):

Transgenic Mice ◽

Bovine Spongiform Encephalopathy ◽

Transgenic Mouse ◽

Neuron Specific Enolase ◽

Infected Sheep ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Wild Type ◽

Spongiform Encephalopathies ◽

Mouse Lines

Transgenic mice expressing the prion protein (PrP) of species affected by transmissible spongiform encephalopathies (TSEs) have recently been produced to facilitate experimental transmission of these diseases by comparison with wild-type mice. However, whilst wild-type mice have largely been described for the discrimination of different TSE strains, including differentiation of agents involved in bovine spongiform encephalopathy (BSE) and scrapie, this has been only poorly described in transgenic mice. Here, two ovine transgenic mouse lines (TgOvPrP4 and TgOvPrP59), expressing the ovine PrP (A136 R154 Q171) under control of the neuron-specific enolase promoter, were studied; they were challenged with brainstem or spinal cord from experimentally BSE-infected sheep (AA136 RR154 QQ171 and AA136 RR154 RR171 genotypes) or brainstem from cattle BSE and natural sheep scrapie. The disease was transmitted successfully from all of these sources, with a mean of approximately 300 days survival following challenge with material from two ARQ-homozygous BSE-infected sheep in TgOvPrP4 mice, whereas the survival period in mice challenged with material from the ARR-homozygous BSE-infected sheep was 423 days on average. It was shown that, in the two ovine transgenic mouse lines, the Western blot characteristics of protease-resistant PrP (PrPres) were similar, whatever the BSE source, with a low apparent molecular mass of the unglycosylated glycoform, a poor labelling by P4 monoclonal antibody and high proportions of the diglycosylated form. With all BSE sources, but not with scrapie, florid plaques were observed in the brains of mice from both transgenic lines. These data reinforce the potential of this recently developed experimental model for the discrimination of BSE from scrapie agents.

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