Spontaneous recombinase activity of Cre–ERT2 in vivo

Kristianto, Jasmin; Johnson, Michael G.; Zastrow, R; Radcliff, Abigail B.; Blank, Robert D.

doi:10.1007/s11248-017-0018-1

Cited by 60 publications

(56 citation statements)

References 13 publications

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“…Indeed, a similar recent study provided similar conclusions [22]. Furthermore, CreER leakiness has previously been observed in both fluorescent reporter and conditional knock‐out studies [23,24], suggesting that this is highly likely a conserved limitation of the CreER system. The authors also exclude that the tamoxifen‐independent recombination was associated to the strong synthetic ‘CAG’ promoter present in some reporter strains.…”

Section: Figuresupporting

confidence: 75%

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems

Stifter

Greter

2020

Eur J Immunol

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Cre and CreER mouse strains are powerful tools that have proven invaluable for investigating the function of genes and for the fate‐mapping of cell populations. The fidelity of these systems however are becoming more and more contested. In this issue of the European Journal of Immunology, Van Hove et al. and Chappell‐Maor et al. carefully dissect the cellular specificities of two commonly used CreER mouse strains for the study of CNS macrophages; Cx3cr1CreER and Sall1CreER. Both studies elegantly highlight that CreER strains, as well as the "floxed" allele to be targeted, need to be carefully selected and properly characterized in order to ensure reproducible and robust data and interpretations. These studies are a cautionary tale for this technology, but also highlight that we must continuously question and improve our experimental approaches.

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Section: Figuresupporting

confidence: 75%

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems

Stifter

Greter

2020

Eur J Immunol

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“…Several dopaminergic neuron-specific Cre recombinase expressing mouse lines (DAT-Cre) have also been created (Backman et al, 2006;Ekstrand et al, 2007;Turiault et al, 2007;Zhuang, Masson, Gingrich, Rayport, & Hen, 2005). Despite concerns about specificity of Cre expression (Papathanou, Dumas, Pettersson, Olson, & Wallen-Mackenzie, 2019) and spontaneous tamoxifen-independent recombination ("leakiness") of CreERT2 (Kristianto, Johnson, Zastrow, Radcliff, & Blank, 2017;Sandlesh, Juang, Safina, Higgins, & Gurova, 2018), these mouse lines have been extremely useful to study functions of multiple genes in dopaminergic neurons. For example, analysis of sonic hedgehog (Shh)/DAT-Cre mice revealed that Shh expression in dopaminergic neurons is essential for their maintenance in the adult animals, as the mutant mice exhibited neurodegeneration, locomotor, and gait abnormalities (Gonzalez-Reyes et al, 2012).…”

Section: Etiological Modelsmentioning

confidence: 99%

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

et al. 2020

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Parkinson's disease (PD) is an age‐related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non‐motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α‐synuclein, LRRK2, DJ‐1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α‐synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD‐like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector‐mediated transgene expression and, recently, injections of misfolded α‐synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre‐clinical PD research towards successful disease‐modifying therapy. © 2020 The Authors.

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“…Many marker genes specific for adult astrocytes are also expressed in NPCs during development (Ferenczy et al, 2013;Foo and Dougherty, 2013), many of which become neurons. This necessitates the employment of inducible strategies, such as CreERT2, although they can be inefficient or hard to tune (Chow et al, 2008;Kristianto et al, 2017). The Slc1a3 gene was used previously to drive Cre using a BAC method whereby a large region of genomic DNA encompassing an entire gene is modified to carry coding sequence for Cre and then returned to the genome where it lands in a random location.…”

Section: Precise Targeting Of Astroglia Is Challengingmentioning

confidence: 99%

Insights into calcium signaling and gene expression in astrocytes uncovered with 129S4 Slc1a3-2A-CreERT2 knock-in mice

Kaczmarczyk

Reichenbach

Blank

et al. 2020

Preprint

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Genetic variation is a primary determinant of phenotypic diversity within populations. In laboratory mice, genetic variation has often been regarded as a serious experimental confounder, and thus minimized through inbreeding. However, generalizations of results obtained with inbred strains need to be made with caution. Effects of genetic background on Kaczmarczyk et al., 2020 129S4 Slc1a3-2A-CreERT2 knock-in mice 2 traits need to be controlled, especially when working with complex phenotypes and disease models. Here we compared behavioral parameters of C57Bl/6 -the mouse strain most widely used for biomedical research -with those of 129S4. Our data demonstrate high within-strain and intra-litter behavioral hyperactivity in C57Bl/6. In contrast, 129S4 had relatively consistent activity levels throughout life. This consistency would be advantageous for studying neurodegeneration and aging, when mice need to be analyzed for long periods. However, the majority of mouse models and transgenic tools are on a C57Bl/6 background. We recently established six popular Cre driver lines and two Cre effector lines in 129S4. To augment this collection, we genetically engineered a Cre mouse line to study astrocytes directly in 129S4, which we describe here. For functional validation, it was crossed with two Cre effector lines, each in a different genomic locus, and showed in both cases that it was functional and astrocyte-specific. Calcium currents studied with gCaMP5g-tdTomato were more heterogenous, lasted longer and had a higher amplitude in cortical compared to hippocampal astrocytes. Translatomes studied with RiboTag revealed that some genes thought to mark neurons are also expressed in astrocytes, that genes linked to a single neurodegenerative disease have highly divergent expression patterns, and that ribosome proteins are nonuniformly expressed across brain regions and cell types.

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Spontaneous recombinase activity of Cre–ERT2 in vivo

Cited by 60 publications

References 13 publications

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems

STOP floxing around: Specificity and leakiness of inducible Cre/loxP systems

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

Insights into calcium signaling and gene expression in astrocytes uncovered with 129S4 Slc1a3-2A-CreERT2 knock-in mice

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