Abstract
The humble house mouse has long been a workhorse model system in biomedical research. The technology for introducing site-specific genome modifications led to Nobel Prizes for its pioneers and opened a new era of mouse genetics. However, this technology was very time-consuming and technically demanding. As a result, many investigators continued to employ easier genome manipulation methods, though resulting models can suffer from overlooked or underestimated consequences. Another breakthrough, invaluable for the molecular dissection of disease mechanisms, was the invention of high-throughput methods to measure the expression of a plethora of genes in parallel. However, the use of samples containing material from multiple cell types could obfuscate data, and thus interpretations. In this review we highlight some important issues in experimental approaches using mouse models for biomedical research. We then discuss recent technological advances in mouse genetics that are revolutionising human disease research. Mouse genomes are now easily manipulated at precise locations thanks to guided endonucleases, such as transcription activator-like effector nucleases (TALENs) or the CRISPR/Cas9 system, both also having the potential to turn the dream of human gene therapy into reality. Newly developed methods of cell type-specific isolation of transcriptomes from crude tissue homogenates, followed by detection with next generation sequencing (NGS), are vastly improving gene regulation studies. Taken together, these amazing tools simplify the creation of much more accurate mouse models of human disease, and enable the extraction of hitherto unobtainable data.
Highlights
Despite their diminutive size, and our lack of body fur and a tail, there are deep, genetically encoded, incontrovertible parallels in human and mouse biology
Mouse genomes are manipulated at precise locations thanks to guided endonucleases, such as transcription activator-like effector nucleases (TALENs) or the Abbreviations 4-TU 4-thiouracil Ago2 Argonaute 2 protein BAC bacterial artificial chromosome Cas9 CRISPR-associated system nuclease 9 CRISPR clustered regularly interspaced short palindromic repeats DSB double strand break ESCs embryonic stem cells Floxed flanked by LoxP sites HR homologous recombination LCM laser capture microdissection next generation sequencing (NGS) generation sequencing NHEJ nonhomologous end joining Prnp prion protein gene RNA guided endonucleases (RGENs) RNA-guided endonucleases RISC RNA-induced silencing complex random integration transgenics (RITs) random integration transgenic Rpl22 ribosomal protein L22 Synthetic guide RNA (sgRNA) synthetic guide RNA TALENs transcription activator-like effector nucleases TALEs transcription activator-like effectors ZFN zinc finger nuclease
The utility of mouse models was dramatically augmented with the advent of recombinant DNA technologies, enabling the modelling of genetic alterations linked to human diseases, and the manipulation of gene networks hypothesised to be involved in disease mechanisms
Summary
The humble house mouse has long been a workhorse model system in biomedical research. The technology for introducing site-specific genome modifications led to Nobel Prizes for its pioneers and opened a new era of mouse genetics. This technology was very time-consuming and technically demanding. Developed methods of cell type-specific isolation of transcriptomes from crude tissue homogenates, followed by detection with generation sequencing (NGS), are vastly improving gene regulation studies. Taken together, these amazing tools simplify the creation of much more accurate mouse models of human disease, and enable the extraction of hitherto unobtainable data
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