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A knockout mouse is a genetically engineered mouse that has had one or more of its genes made inoperable through a gene knockout. Knockout is a route to learning about a gene that has been sequenced but has an unknown or incompletely known function. By inactivating the gene and studying the mouse for any resulting differences, researchers can infer the probable function of that gene. Mice are the laboratory animal species most closely related to humans in which the knockout technique can be easily performed, so they are a favorite subject for knockout experiments, especially with regard to genetic questions that relate to human physiology. Gene knockout in rats is much harder and has only been possible since 2003.
The first knockout mice were produced by Mario R. Capecchi, Martin Evans and Oliver Smithies in 1987–1989, for which they were awarded the Nobel Prize for Medicine in 2007. Aspects of this technology were licensed to Lexicon Pharmaceuticals. The various methods for generating Knockout mice are extensively patented in the United States. The resulting knockout mice can also be patented in many countries.
Additional recommended knowledge
Knocking out the activity of a gene provides information about what that gene normally does. Humans share many genes with mice. Consequently, observing the characteristics of knockout mice gives researchers information that can be used to better understand how a similar gene may cause or contribute to disease in humans.
Examples of research in which knockout mice have been useful include studying and modeling different kinds of cancer, obesity, heart disease, diabetes, arthritis, substance abuse, anxiety, aging and Parkinson's disease. Knockout mice also offer a biological and scientific context in which drugs and other therapies can be developed and tested.
Many of these mouse models are named after the gene that has been inactivated. For example, the p53 knockout mouse is named after the p53 gene which codes for a protein that normally suppresses the growth of tumors by arresting cell division. Humans born with mutations that inactivate the p53 gene suffer from Li-Fraumeni syndrome, a condition that dramatically increases the risk of developing bone cancers, breast cancer and blood cancers at an early age. Other mouse models are named, often with creative flair, according to their physical characteristics or behaviors. For example, "Methuselah" is a knockout mouse model noted for longevity, while "Frantic" is a model useful for studying anxiety disorders.
There are several variations to the procedure of producing knockout mice; the following is a typical example.
A detailed explanation of how knockout (KO) mice are created is located at The Nobel Prize in Physiology or Medicine 2007
While knockout mice technology represents a valuable research tool, some important limitations exist. About 15 percent of gene knockouts are developmentally lethal, which means that the genetically altered embryos cannot grow into adult mice. This problem is often overcome through the use of conditional mutations. The lack of adult mice limits studies to embryonic development and often makes it more difficult to determine a gene's function in relation to human health. In some instances, the gene may serve a different function in adults than in developing embryos.
Knocking out a gene also may fail to produce an observable change in a mouse or may even produce different characteristics from those observed in humans in which the same gene is inactivated. For example, mutations in the p53 gene are associated with more than half of human cancers and often lead to tumors in a particular set of tissues. However, when the p53 gene is knocked out in mice, the animals develop tumors in a different array of tissues.
There is variability in the whole procedure depending largely on the strain from which the stem cells have been derived. Generally cells derived from strain 129 are used. This specific strain is not suitable for many experiments (e.g., behavioral), so it is very common to backcross the offspring to other strains. Some genomic loci have been proven very difficult to knock out. Reasons might be the presence of repetitive sequences, extensive DNA methylation, or heterochromatin.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Knockout_mouse". A list of authors is available in Wikipedia.|