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"I’ve been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, […]” - Raghu Mirmira, MD, PhD University of Chicago.
What are transgenic mice? The short answer is that they’re mice that have been artificially modified at a genetic level to include a foreign sequence, or transgene. This often involves the insertion of a human gene into the mouse’s genome to create a humanized mouse. Methods for creating transgenic mice are versatile, making it possible to create transgenic mice for many different kinds of research. In translational cancer research, transgenic mice are a powerful tool in assessing the potential validity of targeted therapy because the targets can be precisely inactivated in the setting of a developing or developed tumor.
In order to understand transgenic mice, it is first necessary to learn about transgenes. Transgenes are genes that have been taken from one organism and transferred to the genetic makeup of another. For example, a human gene can be copied and transferred to the genetic makeup of a mouse in order to study human disease in a model biological system.
The most common methods of introducing a transgene into an animal model involve genetic manipulation, such as by pronuclear injection of embryos or by homologous recombination in cells. As a result, the use of genetically enhanced transgenic mice has become a crucial part of the science behind finding new treatments for human diseases.
Before the technology was developed to do direct genetic manipulations in animals, selective breeding was used as a means of studying specific genes by selecting and breeding for animals that contained the gene of interest. This trend changed however in the 1970’s with the work of Beatrice Mintz Rudolf Jaenisch: the production of the first transgenic mouse. It was generated by inserting a DNA virus into an early-stage mouse embryo and showing that the inserted genes were present in every cell. Though the transgenic mice did not pass the transgene to their offspring, this began a cascade of experiments by researchers around the world refining methods of germline modification and using these techniques to elucidate the activity and function of genes in a way that was never possible before.
Two basic approaches exist for creating transgenic mice. The first involves delivery of the transgene into a single cell of the mouse embryo via pronuclear injection. Through this method, researchers can overexpress new genes, effectively creating a transgenic mouse. The second method is through the modification of embryonic stem cells via homologous recombination, and the injection of the targeted ES cells into mouse blastocysts.
Using homologous recombination, a more predictable and stable gain-of-function model can be obtained. The most commonly used safe harbor site is the Rosa26 locus because it does not contain any essential genes and provides stable and predictable expression of the transgene in various cell types.
An example of mouse models using the Rosa26 locus and Cre regulated expression is the Npm1 transgenic mouse (the Npm1 mutation, which is the most frequent genetic alteration in acute myeloid leukemia, “AML”). This model has been shown that Npm1 mutations affect megakaryocytic development and mimics some features of human NPM1-mutated AML, thus serving as a good model for further investigations of AML.
In recent years, scientists have been trying to improve the technologies for obtaining transgenic mice. One more recent development is that of CRISPR/Cas9 technology, which can be used to accurately target gene edits in mouse embryos without the need for targeting ES cells first. This system consists of a Cas9 nuclease, which can be directed to any genomic locus by an appropriate single guide RNA (sgRNA).
In addition, the simultaneous injection of Cas9 mRNA and sgRNA into the cytoplasm of zygotes has been shown to efficiently and reliably generate knockout mice with the highest targeting efficiency of all engineered nucleases. Therefore, CRISPR/Cas9 represents an efficient method for generating transgenic mice due to its simplicity, cost-effectiveness, high efficiency, and low fetal toxicity even at relatively high doses of Cas9 mRNA and sgRNA.
The different methods for making mouse lines can be confusing when trying to understand “what are transgenic mice made for.” Generally, transgenic mice are created through random insertion of a gene, while knockin mice involve introducing the gene at a specific locus within the mouse genome. Creating mouse models with the knockin strategy is more complex but removes the unpredictable element that comes with random transgenic insertion. Carefully evaluating the options along with your research plans is crucial to the long-term success of your lab’s research.
“I’ve been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, but the entire process was transparent with the opportunity at any time along the way to discuss my questions or concerns with scientists who had significant insight into the process. The mice were delivered on time, as billed!”
Raghu Mirmira, MD, PhDIndiana University
Over time as you continue to study your gene of interest, you may find that the random insertion that’s inherent in transgenic mice has become an obstacle. A common problem is that it’s better if the mouse gene is knocked out at the same time as the corresponding human gene is expressed. Because the transgene is inserted in a random location, scientists will have to cross the new line with a knockout line and track two alleles throughout their research.
A targeted knockin model can eliminate this additional work by combining expression of the human sequence with knockout of the mouse sequence at a single genomic location. These advantages and others can make this custom transgenic model into a cornerstone of your research for years. Even if you’re focused on your immediate research objectives, a transgenic mouse may be the tool you need.
A new transgenic mouse model generated by random insertion of foreign DNA may enhance your current research. Compared with most models transgenic mice can be created at a relatively low cost and in a shorter amount of time. For example, you can study your gene of interest by generating a transgenic mouse model with its gene expression.
Download Our Free Quick Guide: Rosa26 Knockin Approaches & Targeted Transgenics
Transgenic mice have continued to rise in popularity and are featured in countless scientific papers. A common strategy is to create a humanized line to study a particular human gene or disease. New strains of humanized mice are always being developed to help researchers better understand debilitating diseases such as cancer, Parkinson’s, Alzheimer’s, diabetes, and more. However, there is far more than meets the eye, as transgenic mice can be generated more accurately than ever before with the help of advanced technologies like CRISPR/Cas9.
What are transgenic mice really used for? When considering the drugs that have been developed to treat and control symptoms of a range of diseases, transgenic laboratory mice are an essential tool in the field of genetic research. Cancer, Alzheimer’s disease, inherited disorders and a variety of rare, genetic conditions are more treatable today than ever before, as a result of breakthroughs originally studied in transgenic mice. As a result, the use of genetically enhanced transgenic mice has become a crucial part of the science behind learning more about human disease.
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