Ubiquitous expression of the rtTA2S-M2 inducible system in transgenic mice driven by the human hnRNPA2B1/CBX3 CpG island

Katsantoni, Eleni; Anghelescu, N; Rottier, Robbert J.; Moerland, Matthijs; Antoniou, Michael; Crom, Rini de; Grosveld, Frank; Strouboulis, John

doi:10.1186/1471-213x-7-108

Cited by 31 publications

(40 citation statements)

References 28 publications

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“…We cross-bred this line with an existing hnRNP-rtTA mouse line that expresses a reverse tetracycline-controlled transactivator protein (rtTA) that is activated when mice are treated with dox in drinking water or food. 24 Bigenic offspring with the expanded CGG RNA (TRE-90CGG-eGFP/hnRNP-rtTA) treated with dox in their drinking water (2 mg/ml) or food (1mg/kg) starting at 3 weeks of age, began to lose weight after 2 d of dox treatment. Therefore we stopped dox treatment after 4 d since the mice died after 5 d of treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…TRE-nCGG-eGFP mice were crossed with the hnRNP-rtTA driver line 24 and bigenic mice were treated with dox directly after weaning at an age of 3 weeks. In the initial experiments we treated mice with dox either in food or drinking water, we have not observed any differences between mice treated with dox water or dox food (Bio Services).…”

Section: Construct and Micementioning

confidence: 99%

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Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

et al. 2014

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS.

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Section: Resultsmentioning

confidence: 99%

Section: Construct and Micementioning

confidence: 99%

Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

et al. 2014

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“…HEK293 cells (250,000 cells/well) were plated in 24-well poly-L-lysine-coated plates and grown for 24 h. Cells were co-transfected with pSRE-firefly luciferase (50 ng) (40), pRL-Renilla luciferase (20 ng), pcDNA3.1 containing a full-length human protease-activated receptor (PAR)-2 cDNA (100 ng) (Missouri S&T cDNA Resource Center), pcDNA3.1 containing human matriptase (100 ng), pcDNA3.1 containing human HAI-1 (100 ng), pIRES2-EGFP human prostasin (100 ng) (18), pBig-HAI-2HA (100 ng) and doxycycline inducible rtTA2S-M2 Tet-transactivator, as indicated in the individual experiments (41). Lipofectamine (Invitrogen) was used as the transfection agent according to the manufacturer's instructions.…”

Section: ;Spint1mentioning

confidence: 99%

The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin

Friis

Sales

Schafer

et al. 2014

Journal of Biological Chemistry

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Background: Hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 may regulate matriptase trafficking and activation. Results: Ablation of endogenous HAI-2, but not HAI-1, causes loss of epithelial matriptase in vivo and in vitro, due to uncontrolled prostasin-dependent activation and shedding. Conclusion: HAI-2, but not HAI-1, regulates matriptase cell surface expression level. Significance: The study identifies HAI-2 as a principal regulator of prostasin-mediated matriptase activation.

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“…TetO-Wnt5a mice were interbred with hnRNP-rtTA2S-M2 mice (Katsantoni et al, 2007), obtaining double transgenic mice. Wildtype and single transgenic mice were generated simultaneously and served as control animals.…”

Section: Generation Of Inducible Wnt5a Mouse Model and In Vivo Doxycymentioning

confidence: 99%

“…This promoter is inducible by the rtTA transcription activator in a doxycyline (dox) dependent manner. TetO-Wnt5a founders were crossed with the hnRNP-rtTA transgenic mouse line, which drives ubiquitous expression of the rtTA2S-M2 gene (Katsantoni et al, 2007). Dox administration allows transgenic Wnt5a induction only in double transgenic mice carrying both TetO-Wnt5a and hnRNP-rtTA constructs.…”

Section: Tight Regulation Of Functionally Active Wnt5a Protein In Tetmentioning

confidence: 99%

Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice

Bakker

Raghoebir

Franken

et al. 2012

Developmental Biology

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Wnt5a is essential during embryonic development, as indicated by mouse Wnt5a knockout embryos displaying outgrowth defects of multiple structures including the gut. The dynamics of Wnt5a involvement in these processes is unclear, and perinatal lethality of Wnt5a knockout embryos has hampered investigation of Wnt5a during postnatal stages in vivo. Although in vitro studies have suggested a relevant role for Wnt5a postnatally, solid evidence for a significant impact of Wnt5a within the complexity of an adult organism is lacking. We generated a tightly-regulated inducible Wnt5a transgenic mouse model and investigated the effects of Wnt5a induction during different time-frames of embryonic development and in adult mice, focusing on the gastrointestinal tract. When induced in embryos from 10.5 dpc onwards, Wnt5a expression led to severe outgrowth defects affecting the gastrointestinal tracts, limbs, facial structures and tails, closely resembling the defects observed in Wnt5a knockout mice. However, Wnt5a induction from 13.5 dpc onwards did not cause this phenotype, indicating that the most critical period for Wnt5a in embryonic development is prior to 13.5 dpc. In adult mice, induced Wnt5a expression did not reveal abnormalities, providing the first in vivo evidence that Wnt5a has no major impact on mouse intestinal homeostasis postnatally. Protein expression of Wnt5a receptor Ror2 was strongly reduced in adult intestine compared to embryonic stages. Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2. Taken together, our results indicate a role for Wnt5a during a restricted time-frame of embryonic development, but suggest no impact during homeostatic postnatal stages.

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Ubiquitous expression of the rtTA2S-M2 inducible system in transgenic mice driven by the human hnRNPA2B1/CBX3 CpG island

Cited by 31 publications

References 28 publications

Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin

Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice

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