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Genetically modified mouse

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The genetically modified mouse in which a gene affecting hair growth has been knocked out (left) shown next to a normal lab mouse

Agenetically modified mouse,genetically engineered mouse model(GEMM)[1]ortransgenic mouseis amouse(Mus musculus) that has had itsgenomealtered through the use ofgenetic engineeringtechniques. 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 vivomodels incancer research.Both 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]

History

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In 1974Beatrice MintzandRudolf Jaenischcreated the first genetically modified animal by inserting a DNA virus into an early-stage mouseembryoand showing that the inserted genes were present in every cell.[4]However, the mice did not pass thetransgeneto 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. Brinsterand Richard Palmiter in collaboration from theUniversity of Pennsylvaniaand theUniversity of Washingtoninjected purified DNA into asingle-cell mouse embryoutilizing 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 ofgermlinemodification and using these techniques to elucidate the activity and function of genes in a way not possible before their unique approach.[9]

Methods

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There are two basic technical approaches to produce genetically modified mice. The first involvespronuclear injection,a technique developed and refined byRalph L. Brinsterin 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 atransgenicmouse and is used to insert new genetic information into the mouse genome or to over-expressendogenousgenes. The second approach, pioneered byOliver SmithiesandMario Capecchi,involves modifyingembryonic stem cellswith aDNA constructcontaining DNA sequenceshomologousto the target gene. Embryonic stem cells thatrecombinewith 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 mousecan also be created by direct addition of human genes, thereby creating amurineform ofhuman–animal hybrid.For example, genetically modified mice may be born withhuman leukocyte antigengenes in order to provide a more realistic environment when introducing humanwhite blood cellsinto them in order to studyimmune systemresponses.[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]

Uses

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Transgenic mice expressinggreen fluorescent protein,which glows green under blue light. The central mouse iswild-type.

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 theirtissuesandorgansare 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]The most common type is theknockout mouse,where the activity of a single (or in some cases multiple) genes are removed. They have been used to study and model obesity, heart disease, diabetes, arthritis, substance abuse, anxiety, aging, temperature and pain reception, and Parkinson disease.[16][17]Transgenic mice generated to carry clonedoncogenesand knockout mice lackingtumor suppressing geneshave provided good models for humancancer.Hundreds of theseoncomicehave 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.[18][19]Another mouse has had a gene altered that is involved inglucose metabolismand runs faster, lives longer, is more sexually active and eats more without getting fatter than the average mouse (seeMetabolic supermice).[20][21]Another mouse had theTRPM8 receptorblocked or removed in a study involvingcapsaicinandmenthol.[17]With the TRPM8 receptor removed, the mouse was unable to detect small changes in temperature and the pain associated with it.[17]

Great care should be taken when deciding how to use genetically modified mice in research.[22]Even basic issues like choosing the correct "wild-type" control mouse to use for comparison are sometimes overlooked.[23]

See also

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References

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  1. ^Singh, M.; Murriel, C. L.; Johnson, L. (16 May 2012)."Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes".Cancer Research.72(11): 2695–2700.doi:10.1158/0008-5472.CAN-11-2786.PMID22593194.
  2. ^Abate-Shen, C.; Pandolfi, P. P. (30 September 2013)."Effective Utilization and Appropriate Selection of Genetically Engineered Mouse Models for Translational Integration of Mouse and Human Trials".Cold Spring Harbor Protocols.2013(11): 1006–1011.doi:10.1101/pdb.top078774.PMC4382078.PMID24173311.
  3. ^Sharpless, Norman E.; DePinho, Ronald A. (September 2006)."The mighty mouse: genetically engineered mouse models in cancer drug development".Nature Reviews Drug Discovery.5(9): 741–754.doi:10.1038/nrd2110.ISSN1474-1784.PMID16915232.S2CID7254415.
  4. ^Jaenisch, R.; Mintz, B. (1974)."Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA".Proc. Natl. Acad. Sci.71(4): 1250–1254.Bibcode:1974PNAS...71.1250J.doi:10.1073/pnas.71.4.1250.PMC388203.PMID4364530.
  5. ^Kucherlapati, Raju; Leinwand, Leslie A. (2013)."Frank Ruddle (1929–2013".American Journal of Human Genetics.92(6): 839–840.doi:10.1016/j.ajhg.2013.05.012.PMC3675234.PMID24242788.
  6. ^Gordon, J.; Ruddle, F. (1981). "Integration and stable germ line transmission of genes injected into mouse pronuclei".Science.214(4526): 1244–6.Bibcode:1981Sci...214.1244G.doi:10.1126/science.6272397.PMID6272397.
  7. ^Costantini, F.; Lacy, E. (1981). "Introduction of a rabbit β-globin gene into the mouse germ line".Nature.294(5836): 92–4.Bibcode:1981Natur.294...92C.doi:10.1038/294092a0.PMID6945481.S2CID4371351.
  8. ^Brinster R, Chen HY, Trumbauer M, Senear AW, Warren R, Palmiter RD (1981)."Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs".Cell.27(1 Pt 2): 223–231.doi:10.1016/0092-8674(81)90376-7.PMC4883678.PMID6276022.
  9. ^abDouglas Hanahan; Erwin F. Wagner; Richard D. Palmiter (2007)."The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer".Genes Dev.21(18): 2258–2270.doi:10.1101/gad.1583307.PMID17875663.
  10. ^Gordon, J.W., Scangos, G.A, Plotkin, D.J., Barbosa, J.A. and Ruddle F.H. (1980)."Genetic transformation of mouse embryos by microinjection of purified DNA".Proc. Natl. Acad. Sci. USA.77(12): 7380–7384.Bibcode:1980PNAS...77.7380G.doi:10.1073/pnas.77.12.7380.PMC350507.PMID6261253.{{cite journal}}:CS1 maint: multiple names: authors list (link)
  11. ^Thomas KR, Capecchi MR (1987). "Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells".Cell.51(3): 503–12.doi:10.1016/0092-8674(87)90646-5.PMID2822260.S2CID31961262.
  12. ^Yong KS, Her Z, Chen Q (August 2018)."Humanized Mice as Unique Tools for Human-Specific Studies".Archivum Immunologiae et Therapiae Experimentalis.66(4): 245–266.doi:10.1007/s00005-018-0506-x.PMC6061174.PMID29411049.
  13. ^"Mouse strain C57BL/6-Mcph1Tg(HLA-A2.1)1Enge".The Jackson Laboratory.Retrieved2023-01-06.
  14. ^"Background: Cloned and Genetically Modified Animals".Center for Genetics and Society. April 14, 2005. Archived fromthe originalon November 23, 2016.RetrievedJuly 11,2010.
  15. ^abcHofker, Marten H.; Deursen, Jan van (2002).Transgenic Mouse.Totowa, New Jersey: Humana Press. pp.1.ISBN0-89603-915-3.
  16. ^"Knockout Mice".Nation Human Genome Research Institute. 2009.
  17. ^abcJulius, David."How peppers and peppermint identified sensory receptors for temperature and pain".iBiology.Retrieved2020-05-14.
  18. ^McPherron, A.; Lawler, A.; Lee, S. (1997). "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member".Nature.387(6628): 83–90.Bibcode:1997Natur.387...83M.doi:10.1038/387083a0.PMID9139826.S2CID4271945.
  19. ^Elisabeth R. Barton-Davis; Daria I. Shoturma; Antonio Musaro; Nadia Rosenthal; H. Lee Sweeney (1998)."Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function".PNAS.95(26): 15603–15607.Bibcode:1998PNAS...9515603B.doi:10.1073/pnas.95.26.15603.PMC28090.PMID9861016.
  20. ^"Genetically engineered super mouse stuns scientists".AAP.November 3, 2007.
  21. ^Hakimi P, Yang J, Casadesus G, Massillon D, Tolentino-Silva F, Nye C, Cabrera M, Hagen D, Utter C, Baghdy Y, Johnson DH, Wilson DL, Kirwan JP, Kalhan SC, Hanson RW (2007)."Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse".Journal of Biological Chemistry.282(45): 32844–32855.doi:10.1074/jbc.M706127200.PMC4484620.PMID17716967.
  22. ^Crusio, W.E.;Goldowitz, D.; Holmes, A.; Wolfer, D. (2009)."Standards for the publication of mouse mutant studies".Genes, Brain and Behavior.8(1): 1–4.doi:10.1111/j.1601-183X.2008.00438.x.PMID18778401.S2CID205853147.
  23. ^Mohammed Bourdi; John S. Davies; Lance R. Pohl (2011)."Mispairing C57BL/6 Substrains of Genetically Engineered Mice and Wild-Type Controls Can Lead to Confounding Results as It Did in Studies of JNK2 in Acetaminophen and Concanavalin A Liver Injury".Chemical Research in Toxicology.24(6): 794–796.doi:10.1021/tx200143x.PMC3157912.PMID21557537.
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