Science Simplified: What Are Genetic Mouse Models and How Can They Help Us Study Genetic Diseases And Develop Treatments?

Want to learn about scientific topics without needing a PhD? Check out the Science Simplified blog from TESS Research Foundation! Dr. Tanya Brown, PhD, works with researchers to make science accessible and empower rare disease community members with scientific knowledge. Dr. Brown has over a decade of experience in neurodevelopmental research and is currently the Scientific Director for TESS Research Foundation. Please reach out to her at tanya@tessfoundation.org if you have questions or comments.

Thank you to Vanessa L. Hull for writing this story. Vanessa is a neuroscience graduate student at the University of California, Davis who is working on developing therapies for Canavan disease. You can follow her on Twitter: @neuroneska.

Scientists have many experimental models at their disposal to study genetic diseases, such as taking a sample of a patient’s cells and growing them in a dish. However, as you might imagine, cells in a dish can only offer a limited perspective when trying to understand the complex way in which a disease might impact multiple systems within an organism. They also offer little insight on how the immune system might react to investigational therapies.

One of the best ways to study a disease and test potential treatments is by using model organisms. A common model organism is the mouse. Mice are especially useful for studying genetic diseases because they breed quickly and easily, and we have become very skillful at modifying their genes to create genetic mouse models. DNA, as you may already know, comes in functional units called genes. A gene is just a sequence of code that contains instructions for making specific proteins, like the SLC13A5 gene which provides instructions for how to make the NaCT protein that moves citrate from outside a cell to inside the cell’s citrate transporter protein. Using DNA editing technology, we can modify mouse embryos to delete, modify, or insert genes of interest, giving us the opportunity to create disease models with similar (or even identical) genetic mutations to those seen in human diseases. This article will discuss what we can learn from genetic mouse models, some different types of models, and models that are currently available to study SLC13A5.

What sorts of things can we learn from genetic mouse models?

Genetic mouse models can help us:

  • observe how cells change in a disease environment
  • understand the function of a gene (and the protein it produces) and its role in important biological pathways
  • observe how a disease progresses over time
  • observe motor or cognitive changes using behavioral tests
  • understand how certain proteins interact with one another, pointing to new therapeutic targets
  • test investigational therapies in a holistic way, including understanding:
    • how an organism’s immune system might react to a novel treatment
    • what impact a therapy might have on organ systems outside of the targeted region

What different kinds of genetic mouse models are there and how do they work?

There are four main types of genetic mouse models (described in Figure 1):

  1. Constitutive knockout mice
  2. Conditional knockout mice
  3. Knockin mice
  4. Reporter mice

The most common form is the knockout mouse, which includes mice who have had one or more target genes deleted from their genome. Knockout mice can come in two forms: constitutive or conditional.

Constitutive knockout mice never express the deleted gene in any of their cells and for this reason they are often referred to as “global knockout mice”. Without this target gene in their genome, they lack the instructions to create the protein typically made/produced by this gene, so these mice end up with no functional protein product. Constitutive knockout mice are a great tool for studying human diseases that result from these sorts of so-called “loss of function” genetic mutations.

In contrast, conditional knockout mice will have a target gene deleted from only a subset of cells or tissue. Perhaps a gene is critical for survival when expressed in the central nervous system, so it cannot safely be deleted from these cells. However, if we only delete it from the cardiovascular system, perhaps we can create a very useful mouse model for heart disease. Conditional knockout mice also offer the opportunity to turn off specific genes at specific times during development, which can help model diseases that start later in life or the aging processes. In this way, conditional knockout mice offer us the ability to control both when and where a gene is being deleted.

Perhaps instead of deleting a gene we want to introduce a gene that is not normally expressed in the mouse; this is where knockin mice come in handy. This model is a superb tool for studying a gene’s function, but it is also very useful in cases where the mouse version of a gene is quite a bit different from the human gene, as is the case with SLC13A5 Epilepsy (we’ll talk more about this at the end of the article).

Lastly, we have the very popular reporter mouse. Scientists need a way to label individual cells so they can see them under the microscope. Reporter mice are engineered to express fluorescent or colored proteins within certain cell types so that we can easily distinguish them from other cells. One of the most common labels is Green Fluorescent Protein or GFP for short. Under a special microscope, you can see all the cells labeled with GFP because they glow green! We can also attach different fluorescent proteins (red, blue, and yellow fluorescent proteins) to proteins of interest, allowing us to better understand a protein’s function and observe what else it might interact with. All of this information will help lead us to potential targets for therapy.

Let’s walk through an example of how you might use a reporter mouse. If you are studying a disease that affects the brain, such as SLC13A5 Epilepsy, scientists could use a reporter mouse to label certain types of cells found in the brain, such as neurons. Using a neuron reporter mouse (Neuron-GFP), in combination with a knockout mouse (SLC13A5 Knockout), will allow scientists to ask important questions about the disease such as:

  • Are there too many neurons?
  • Are there too few neurons?
  • Are the neurons found in the proper location in the brain?
  • Have the neurons changed their appearance or how they signal to one another?

Some reporter mice express green fluorescent protein in all of their cells, so that if we transplant cells from this mouse into another mouse, we can easily distinguish between the introduced cells (which will glow green!) and the cells of the host. These transplant experiments can allow us to determine whether cells carrying a specific mutation can cause other cells in a healthy environment to start behaving differently, or if the effect only occurs in cells with the mutation. This allows us to distinguish whether something is self-induced (a cell-autonomous effect) or caused by external factors (non-cell autonomous behavior).

What type of mouse models exist to study SLC13A5 Epilepsy?

Some forms of SLC13A5 Epilepsy result from mutations that stop the production of any functional protein product (the NaCT citrate transporter). This form of SLC13A5 Epilepsy is modeled by the constitutive SLC13A5 knockout mouse, which allows us to observe how global loss of the NaCT transporter affect all systems of the mouse (such as elevated citrate levels) and even its behavior. This constitutive knockout model is currently being used in pre-clinical studies to test the efficacy and tolerability of SLC13A5 gene therapy. There are also SLC13A5 conditional knockout mice available as well to study how a lack of SLC13A5 affects different cell types.

Mouse models also offer us the ability to study how the immune system of an animal might respond to new therapies, an essential consideration for investigational treatments. TESS Research Foundation was also recently awarded an exciting grant from the Orphan Disease Center to develop a humanized knockin SLC13A5 mouse model, where the mouse form of SLC13A5 will be replaced with the human form, which we can use to study the disease in new and important ways.

You may be curious about the ethical considerations of using animal models. Though we won’t cover this topic in detail here, it is important to keep in mind that all animal research is monitored at the local, state and national level. All protocols are examined and approved by strict review boards and all animals are under the care of highly trained veterinary staff. You can learn more about animal research here: Animals in Research and Teaching at UC Davis and NIH Grants & Funding’s Policy & Compliance page about Animals in NIH Research.

We want to hear from you! If you want to add to our list of topics for Science Simplified, please email Tanya Brown, PhD: tanya@tessfoundation.org.

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