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Mouse models provide insights into the causal mechanisms of diseases

Small differences in our genome distinguish us from each other. Although diversity is a good thing, many diseases are caused by genetic variants. Due to the around 80-percent similarity between the mouse and human genome, mice are of great assistance in the study of human diseases. Mouse strains can therefore be used to build models of genetic diseases that affect humans. Such models can be used to study the causal mechanisms of diseases and to design drugs.

 

The European INFRAFRONTIER research infrastructure offers over 6,800 mutant mouse strains, i.e. strains that model thousands of different diseases.The infrastructure has 23 member organisations. Finland is represented by Biocenter Oulu at the University of Oulu.

The Nobel Prize in Physiology or Medicine 2007 was jointly awarded to Mario R. Capecchi, Sir Martin J. Evans and Oliver Smithies for discoveries, which enable stem cells to be used to create germline modifications and additions into a mouse’s genome. Evans developed a technique for growing mouse-embryo stem cells. He implanted the stem cells into mouse embryos, which then developed into mice composed of cells with two distinct genotypes. In other words, stem cells could be used to include genetic material from one mouse to another. The hybrid mice develop normally at cellular level.

Capecchi and Smithies developed a procedure for silencing the expression of a certain mouse gene by transferring foreign DNA to a precisely targeted part of the mouse’s genome. The foreign DNA either knocks out or extensively decreases the expression of the gene, enabling scientists to identify which gene affects which mouse characteristic. Stem cells from a mouse embryo were used to create a mouse model with targeted silencing of genes. In this way, a hybrid mouse was created whose offspring were full ‘knockout’ mice, i.e. a gene function had been knocked out from their genome. This technique has now largely been replaced by the CRISPR-Cas9 method.

Being able to silence a single gene in a mouse enables studying the effect of switching off the gene in question. This has allowed the identification of genes that determine phenomena such as the development of mammalian bone structure and certain internal organs.

 

Mouse models in the study of disease mechanisms

 

INFRAFRONTIER nodes, such as Biocenter Oulu, engage in the cryopreservation, archiving and distribution of mouse strains. Photo: Mikko Törmänen

 

Genome editing has enabled the creation of mouse models of several human diseases. Such models can be used to study the causal mechanisms, progression and, of course, the treatment of diseases.

“If a new mutation or disease is found in a patient, we see only the clinically defined symptoms of the disease. If a disease has reached the late stage or has multiple symptoms, it is difficult to distinguish the primary cause from secondary effects,” says Adjunct Professor Reetta Hinttala from Biocenter Oulu.

Hinttala is the Coordinator of the Transgenic Core Facility at Biocenter Oulu. The facility is part of the European INFRAFRONTIER infrastructure. INFRAFRONTIER provides researchers around the world with access to mouse models for the study of genomes and diseases.

Within the Faculty of Medicine’s PEDEGO Research Unit at the University of Oulu, Reetta Hinttala uses mouse models to study rare inherited diseases. Mouse models help to identify the genes causing illnesses.

“Mouse models are a key element in gene research. They enable scientists to study disease genes and mechanisms at organism level. A model provides basic information on how a disease progresses. By studying mice of various ages, we can discover what happens in different tissues during each stage of a disease.”

Hinttala explains that it would be difficult to perform similar tissue-level analyses on samples from human patients, particularly for diseases of the central nervous system.

”An animal model provides valuable information on events at tissue level during the earliest stages of a disease. They may be of a kind that would go unnoticed in humans. Targeting research at early changes of this kind enables the discovery of early-stage treatments, which can be used in future pharmaceutical development.”

Hinttala points out that mouse models are particularly important when studying poorly characterized proteins and disease mechanisms. They enable the study of pathological changes at the tissue level during a disease’s progression in their proper environment. The similarity between the mouse and human genome allows observation of the same fundamental disease-causing mechanisms in mice and humans.

 

Tissue imaging requires memory space

 

 

Tissue is composed of multiple cell types and their surrounding extracellular matrix. Researchers in Oulu are investigating histopathological structures of tissues and how they are organised to form organs. A microscope capable of imaging structural features of the tissue in detail is a key tool in the collection of data. New information is gathered on tissue samples by using various staining techniques to visualise chosen structures or molecules.

Digital images of tissue samples are tagged with metadata and archived. However, the storage and sharing of the imaging data is challenging. An image file of a tissue section scanned using a Slide Scanner can be several dozen gigabytes in size. Ensuring the future management of files of this size is challenging.

While researchers have an increasing need to store image material, they also need to be able to describe the data, to enable its distribution to the scientific community.

”Both INFRAFONTIER and the ELIXIR infrastructures are working to promote access to open research data. To make data derived from mice maximally available, it must be processed and analysed to become suitable for research purposes. I also think that describing imaging data in line with international standards – which enables the further use of images for purposes such as combining data with supplementary data sources – is an important line of work,” says Tommi Nyrönen of CSC, Head of Node of the Finnish ELIXIR centre.

 

EMMA is an extensive mouse model archive

 

In vitro fertilisation in mice on the dish. Stereomicroscope shown in the picture. Photo: Mikko Törmänen.

 

Europe’s scientifically important mouse strains are kept in INFRAFRONTIER’s EMMA repository, one of the world’s leading mouse strain repositories. EMMA (The European Mutant Mouse Archive) archives genetically modified mouse strains from all over the world, free of charge. EMMA currently holds 6,800 mutated mouse strains, i.e. mouse models, many of which have been connected to diseases. The operations of Infrafrontier’s various nodes are organised via a centre in Munich. Located in 12 different countries, the nodes engage in the cryopreservation, archiving and distribution of mouse strains. Some of the nodes also phenotype mouse strains.

”Researchers can preserve their own mouse strains, or mouse models, in the repository, if the strain is sufficiently well characterised and a certain mutation has been reliably verified. When a new mouse strain is accepted for the EMMA repository, the researcher sends the mice to a selected node. INFRAFRONTIER’s website includes a search tool for exploring which mouse strains are currently archived. A cryopreserved strain can later be rederivated, resulting in a live mouse.”

A total of 226 mouse strains are cryopreserved at Finland’s EMMA unit in Oulu. They include a mouse model of the rare FINCA disease (discovered by Reetta Hinttala and Johanna Uusimaa, Professor of Paediatric Neurology). The NHLRC2 gene has been silenced in this model. The NHLRC2 protein was discovered to be vital to normal foetal development and several organ functions.

 

Phenotyping describes a mouse model

 

Samples frozen in liquid nitrogen. Photo: Mikko Törmänen

Phenotype classification is done on the basis of the mouse’s symptoms and other characteristics. Systematic analyses are used to determine the effects of a genetic modification on a mouse. Such analyses thereby describe the mouse model in question.

”Analyses of this kind are performed in mouse clinics, in which advanced analysis and diagnostics techniques are used to study genotype-phenotype interactions,” explains Hinttala.

Through Infrafrontier, researchers have the opportunity to use the services of the German Mouse Clinic and the worldwide International Mouse Phenotyping Consortium (IMPC). The IMPC generates phenotyping data from mice, in which one of the 20,000 or so genes has been knocked out, to aid studies on disease mechanisms.

Phenotyping is also needed at national level. Reetta Hinttala is the chair of the FinGMice platform, which is part of Biocenter Finland. Together, Biocenter Finland’s four locations in Helsinki, Turku, Kuopio and Oulu provide a comprehensive and diverse mouse phenotyping network.

Transgenic Core Facility, Biocenter Oulu. Photo: Mikko Törmänen

”The aim is to guarantee researchers access to services, equipment and analysis support in both primary and secondary phenotyping. For this reason, it is very important to be able to transfer for example large image files of tissue sections between universities, so that we can consult experts all over Finland when needed.”

Ari Turunen

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https://www.infrafrontier.eu

http://www.mousephenotype.org

http://www.fingmice.org

https://www.oulu.fi/biocenter/core-facilities