2015 Guidelines for Establishing Genetically Modified Rat Models for Cardiovascular Research

Flister, Michael J.; Prokop, Jeremy W.; Lazar, Jozef; Shimoyama, Mary; Dwinell, Melinda R.; Geurts, Aron M.

doi:10.1007/s12265-015-9626-4

Cited by 20 publications

(9 citation statements)

References 77 publications

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“…Moreover, our Drd1 I116S mutant rat has an outbred Wistar background, which might substantially alter Drd1 epistatic effects and approach human genetic heterogeneity to a larger extent. Finally, with the current expansion of genetic tools to manipulate the rat genome, including zinc finger nuclease, transcription activator-like effector nucleases (TALEN) and CRISPR/CAS9, ENU mutagenesis as a technology to generate mutant rat models might seem outdated (Flister et al, 2015; Parker et al, 2014). Although these more recent technologies, unlike ENU mutagenesis, allow targeted mutations, the advantage brought about by ENU mutagenesis is that it induces random mutations, not only premature stop codons and thereby knockout rats, but also hypothesis-free point mutations causing amino acid exchanges (Smits et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model

Homberg

Olivier

VandenBroeke

et al. 2016

Disease Models &Amp; Mechanisms

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Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction.

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Section: Discussionmentioning

confidence: 99%

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model

Homberg

Olivier

VandenBroeke

et al. 2016

Disease Models &Amp; Mechanisms

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“…In the past two decades, to uncover the molecular mechanisms of cardiac aging, many transgenic, gene knockout, pro-aging, and anti-aging mouse models have been generated, and the research of cardiac aging has been much improved with the help of these whole mouse models [1–3]. In contrast, the progress of senescence models of mouse cardiac myocytes in cultured cells in vitro is still very slow, although the cell models are critical for the mechanistic studies of cardiac aging.…”

mentioning

confidence: 99%

A Natural Model of Mouse Cardiac Myocyte Senescence

Wang

Rong

Luo

et al. 2016

J. of Cardiovasc. Trans. Res.

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Many cardiac aging studies are performed on mice first and then, due to difficulty in mouse cardiomyocyte culture, applied the rat neonatal cardiomyocytes to further determine the mechanisms in vitro. Now, the technological challenge of mouse cardiomyocyte culture has been overcome and there is an increasing need for the senescence models of mouse cardiomyocytes. In this study, we have demonstrated that the senescence of mouse cardiomyocytes occurred with the extended culture time as shown by the increased β-galactosidase staining, increased p53 expression, decreased telomere activity, shorted telomere length, increased production of ROS, increased cell apoptosis, and impaired mitochondrial ΔΨm. These senescent responses shared similar results in aged mouse heart tissues in vivo. In summary, we have established and characterized a novel senescence model of mouse cardiomyocytes induced by the extended culture time in vitro. The cell model could be useful for the increased cardiac aging studies worldwide.

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“…This additional sequence tag, typically 5′-NGG-3′, ensures that in bacteria the system recognises invading PAM-containing DNA, but not host CRISPR-associated protospacer DNA that lacks adjacent PAMs. Since the frequency of 5′-NGG-3′ PAM sequence in the AT-rich rat genome occurs on average every 16–18 bp, much of the rat genome is accessible to CRISPR/Cas-directed gene editing, although in some instances this may prove limiting for knock-in strategies which require the cut site to be less than 20 bp from the intended insertion site (Flister et al 2015 ). Furthermore, the short recognition sequence of the CRISPR/Cas system may restrict the targeting of repetitive sequences and closely related genes containing similar sequences.…”

Section: Crispr/cas Gene Editingmentioning

confidence: 99%

From engineering to editing the rat genome

2017

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Since its domestication over 100 years ago, the laboratory rat has been the preferred experimental animal in many areas of biomedical research (Lindsey and Baker The laboratory rat. Academic, New York, pp 1–52, 2006). Its physiology, size, genetics, reproductive cycle, cognitive and behavioural characteristics have made it a particularly useful animal model for studying many human disorders and diseases. Indeed, through selective breeding programmes numerous strains have been derived that are now the mainstay of research on hypertension, obesity and neurobiology (Okamoto and Aoki Jpn Circ J 27:282–293, 1963; Zucker and Zucker J Hered 52(6):275–278, 1961). Despite this wealth of genetic and phenotypic diversity, the ability to manipulate and interrogate the genetic basis of existing phenotypes in rat strains and the methodology to generate new rat models has lagged significantly behind the advances made with its close cousin, the laboratory mouse. However, recent technical developments in stem cell biology and genetic engineering have again brought the rat to the forefront of biomedical studies and enabled researchers to exploit the increasingly accessible wealth of genome sequence information. In this review, we will describe how a breakthrough in understanding the molecular basis of self-renewal of the pluripotent founder cells of the mammalian embryo, embryonic stem (ES) cells, enabled the derivation of rat ES cells and their application in transgenesis. We will also describe the remarkable progress that has been made in the development of gene editing enzymes that enable the generation of transgenic rats directly through targeted genetic modifications in the genomes of zygotes. The simplicity, efficiency and cost-effectiveness of the CRISPR/Cas gene editing system, in particular, mean that the ability to engineer the rat genome is no longer a limiting factor. The selection of suitable targets and gene modifications will now become a priority: a challenge where ES culture and gene editing technologies can play complementary roles in generating accurate bespoke rat models for studying biological processes and modelling human disease.

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2015 Guidelines for Establishing Genetically Modified Rat Models for Cardiovascular Research

Cited by 20 publications

References 77 publications

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model

A Natural Model of Mouse Cardiac Myocyte Senescence

From engineering to editing the rat genome

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