Agenetically modified mouse,genetically engineered mouse model (GEMM)[1] ortransgenic mouse is amouse (Mus musculus) that has had itsgenome altered through the use ofgenetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases and are also used for research on genes. Together withpatient-derived xenografts (PDXs), GEMMs are the most commonin vivo models incancer research. The two approaches are considered complementary and may be used to recapitulate different aspects of disease.[2] GEMMs are also of great interest fordrug development, as they facilitate target validation and the study of response, resistance, toxicity andpharmacodynamics.[3]
In 1974Beatrice Mintz andRudolf Jaenisch created the first genetically modified animal by inserting a DNA virus into an early-stage mouseembryo and showing that the inserted genes were present in every cell.[4] However, the mice did not pass thetransgene to their offspring, and the impact and applicability of this experiment were, therefore, limited. In 1981 the laboratories ofFrank Ruddle[5] fromYale University, Frank Costantini and Elizabeth Lacy fromOxford, andRalph L. Brinster and Richard Palmiter in collaboration from theUniversity of Pennsylvania and theUniversity of Washington injected purified DNA into asingle-cell mouse embryo utilizing techniques developed by Brinster in the 1960s and 1970s, showing transmission of the genetic material to subsequent generations for the first time.[6][7][8] During the 1980s, Palmiter and Brinster developed and led the field of transgenesis, refining methods ofgermline modification and using these techniques to elucidate the activity and function of genes in a way not possible before their unique approach.[9]
There are two basic technical approaches to produce genetically modified mice. The first involvespronuclear injection, a technique developed and refined byRalph L. Brinster in the 1960s and 1970s, into a single cell of the mouse embryo, where it will randomly integrate into the mouse genome.[10] This method creates atransgenic mouse and is used to insert new genetic information into the mouse genome or to over-expressendogenous genes. The second approach, pioneered byOliver Smithies andMario Capecchi, involves modifyingembryonic stem cells with aDNA construct containing DNA sequenceshomologous to the target gene. Embryonic stem cells thatrecombine with the genomic DNA are selected for and they are then injected into the miceblastocysts.[11] This method is used to manipulate a single gene, in most cases"knocking out" the target gene, although increasingly more subtle and complex genetic manipulation can occur (e.g. humanisation of a specific protein, or only changing singlenucleotides). Ahumanised mouse can also be created by direct addition of human genes, thereby creating amurine form ofhuman–animal hybrid. For example, genetically modified mice may be born withhuman leukocyte antigen genes in order to provide a more realistic environment when introducing humanwhite blood cells into them in order to studyimmune system responses.[12] One such application is the identification ofhepatitis C virus (HCV) peptides that bind to HLA, and that can be recognized by the human immune system, thereby potentially being targets for future vaccines against HCV.[13]
Genetically modified mice are used extensively in research as models of human disease.[14] Mice are a useful model for genetic manipulation and research, as theirtissues andorgans are similar to that of a human and they carry virtually all the same genes that operate in humans.[15] They also have advantages over other mammals, in regards to research, in that they are available in hundreds of genetically homogeneous strains.[15] Also, due to their size, they can be kept and housed in large numbers, reducing the cost of research and experiments.[15] Transgenic mice are found in two main models of either loss or gain of function. The most common type is loss of function mice or theknockout mouse, where the activity of a single (or in some cases multiple) genes are removed or silenced. Gain of function mice, in other hand, overexpress a specific gene.[16] They have been used to study and model obesity, heart disease, diabetes, arthritis, substance abuse, anxiety, aging, temperature, pain reception, andParkinson's disease.[17][18] Genetically modified mice further be divided into constitutive mouse model, in which the target gene is permanently activated or inactivated in all the cells of the animal, or conditional mouse model, in which the knockout or the overexpressed gene can be regulated in a spatiotemporal manner, which enables targeting of a specific type or subset of cells in the animal from a specific time in the life of the animal.[16]
Transgenic mice generated to carry clonedoncogenes and knockout mice lackingtumor suppressing genes have provided good models for humancancer.[19][20] Hundreds of theseoncomice have been developed covering a wide range of cancers affecting most organs of the body and they are being refined to become more representative of human cancer.[9] The disease symptoms and potential drugs or treatments can be tested against these mouse models.
A mouse has been genetically engineered to have increased muscle growth and strength by overexpressing theinsulin-like growth factor I (IGF-I) in differentiatedmuscle fibers.[21][22] Another mouse has had a gene altered that is involved inglucose metabolism and runs faster, lives longer, is more sexually active and eats more without getting fatter than the average mouse (seeMetabolic supermice).[23][24] Another mouse had theTRPM8 receptor blocked or removed in a study involvingcapsaicin andmenthol.[18] With the TRPM8 receptor removed, the mouse was unable to detect small changes in temperature and the pain associated with it.[18]
Great care should be taken when deciding how to use genetically modified mice in research.[25] Even basic issues like choosing the correct "wild-type" control mouse to use for comparison are sometimes overlooked.[26]
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