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Genetically modified mouse

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

A genetically modified mouse is a mouse that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases.

History

In 1974 Rudolf Jaenisch created the first genetically modified animal by inserting a DNA virus into an early-stage mouse embryo and showing that the inserted genes were present in every cell.[1] However the mice did not pass the transgene to their offspring. In 1981 the laboratories of Frank Ruddle from Yale and Frank Constantini and Elizabeth Lacy in Oxford injected purified DNA into a single-cell mouse embryo and showed transmission of the genetic material to subsequent generations.[2][3] During the early eighties the technology used to generate genetically modified mice was improved into a tractable and reproducible method.[4]

Methods

There are two basic technical approaches to produce genetically modified mice. The first involves pronuclear injection into a single cell of the mouse embryo, where it will randomly integrate into the mouse genome.[5] This method creates a transgenic mouse and is used to insert new genetic information into the mouse genome or to over-express endogenous genes. The second approach involves modifying embryonic stem cells with a DNA construct containing DNA sequences homologous to the target gene. Embyonic stem cells that recombine with the genomic DNA are selected for and they are then injected into the mice blastocysts.[6] This method is used to manipulate a single gene, in most cases "knocking out" the target gene, although more subtle genetic manipulation can occur (e.g. only changing single nucleotides).

Uses

Transgenic mice expressing green fluorescent protein, which glows green under blue light. The central mouse is wild-type.

Genetically modified mice are used extensively in research as models of human disease.[7] The most common type is the knockout 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 and Parkinson disease.[8] Transgenic mice generated to carry cloned oncogenes and knockout mice lacking tumor suppressing genes have provided good models for human cancer. Hundreds of these oncomice 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.[4] 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 the insulin-like growth factor I (IGF-I) in differentiated muscle fibers.[9][10] Another mouse has had a gene altered that is involved in glucose metabolism and runs faster, lives longer, is more sexually active and eats more without getting fat than the average mouse (see Metabolic supermice).[11][12]

Great care should be taken when deciding how to use genetically modified mice in research.[13] Even basic issues like choosing the correct "wild-type" control mouse to use for comparison are sometimes overlooked.[14]

References

  1. ^ Jaenisch, R. and 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. PMC 388203. PMID 4364530.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1126/science.6272397, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1126/science.6272397 instead.
  3. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/294092a0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/294092a0 instead.
  4. ^ a b Douglas Hanahan, Erwin F. Wagner and 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. PMID 17875663.
  5. ^ 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. PMC 350507. PMID 6261253.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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. PMID 2822260.
  7. ^ "Background: Cloned and Genetically Modified Animals". Center for Genetics and Society. April 14, 2005.
  8. ^ "Knockout Mice". Nation Human Genome Research Institute. 2009.
  9. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/387083a0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/387083a0 instead.
  10. ^ Elisabeth R. Barton-Davis, Daria I. Shoturma, Antonio Musaro, Nadia Rosenthal, and 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. PMC 28090. PMID 9861016.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ "Genetically engineered super mouse stuns scientists". AAP. November 3, 2007.
  12. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1074/jbc.M706127200, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1074/jbc.M706127200 instead.
  13. ^ 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. PMID 18778401.
  14. ^ 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. PMC 3157912. PMID 21557537.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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