Huntington's disease research and drug testing frequently involve the use of mouse models. However, when different scientists refer to an HD mouse model they may not be referencing the same model. A variety of HD mouse models exist and are used regularly. This chapter will describe the most common HD mouse models, how they differ, and the ways in which they mimic the disease.
This article makes reference to both the mouse and the human huntington gene. The mouse huntington gene is a homolog of the human huntington gene, but there are subtle differences between them. For example, the mouse huntington gene has fewer CAG repeats than the normal human huntington gene, explaining why spontaneous mouse models of the disease do not exist. Despite this difference, the mouse huntington gene is 81% similar to the human huntington gene at the DNA level, showing that the two are true homologs. Different mouse models have been generated since the isolation of the HD gene in 1993. There are three general types of mouse model: knockout, transgenic, and knock-in.
Knockout models were the first models to be generated. These are models where the gene coding for the huntingtin protein (the mouse huntington gene) is removed or interrupted so that the DNA can not be transcribed. Although these models provide valuable scientific insights, they do not actually represent the disease because mice that are nullizygous for the huntington gene die during embryogenesis.
Transgenic models are made when the mutant human huntington gene, or a fragment of that gene, is inserted into the nuclei of a model organism. In transgenic models the gene insertion is not targeted to a specific location in the animal genome, meaning that where the gene inserts itself cannot be predicted. For a mouse model, this means that the mouse will express both the two normal copies of the mouse huntington gene as well as the human mutant gene or fragment that was inserted into its genome. It also means that the expression of the inserted mutant human huntington gene will not be controlled by the homologous promoter region of the mouse huntington gene. This frequently leads to much higher protein expression than normal endogenous levels.
Knock-in mice have either part of or the entire human mutant huntington gene inserted in place of part of or the entire endogenous mouse gene. Knock-in mice, therefore, carry the expanded CAG repeat mutation in the same place in the genome that it would appear if it were to develop naturally. This is the most faithful model in the sense that the mutant gene is located in the appropriate genomic context and will have the normal promoter region associated with the huntingtin protein. Knock-in mouse models can be either homozygous or heterozygous for the huntingtin mutation.
To learn more about the process of creating genetically modified model animals click here .
The remainder of this chapter considers the following topics:
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