This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What are model organisms and why are they useful?
Model organisms are species that have been widely studied in a laboratory setting and are organisms that have well-characterized genomes. Scientists use model organisms very frequently in genetic research and they allow them to study human diseases without doing studies on actual humans. Some common model organisms in genetic research include:
- Yeast (Saccharomyces cerevisiae)
- Fruit fly (Drosophila melanogaster)
- Nematode worm (Caenorhabditis elegans)
- Western clawed frog (Xenopus tropicalis)
- Mouse (Mus musculus)
- Zebrafish (Danio rerio)
What model organisms are best for studying CNBP & DM2?
Since myotonic dystrophy type 2 (DM2) is a disease characterized by progressive muscle loss and muscle wasting, using a model organism with similar skeletal and heart muscles allows researchers to directly observe these phenotypes. As seen on the Homology page of this website, the CNBP protein is highly conserved across mammals, and more specifically, it is very highly conserved in mice. Mus musculus or mice are advantageous to use as model organisms since they are relatively cheap and easy to house, easy to handle, and have well-characterized anatomy and physiology that is comparable to humans [2].
In addition to these general advantages, mice are also great DM2 model organisms due to the fact that mice exhibit many of the same DM2 phenotypes that have been observed in humans. Mice exhibiting the DM2 muscle phenotypes of muscle wasting and muscle weakness can be generated in the lab by simply eliminating one CNBP gene copy, thereby rendering them haploinsufficient [3]. Figure 1 depicts the some mice phenotypes found in the wild-type (+/+) and disease (+/-) states.
In addition to these general advantages, mice are also great DM2 model organisms due to the fact that mice exhibit many of the same DM2 phenotypes that have been observed in humans. Mice exhibiting the DM2 muscle phenotypes of muscle wasting and muscle weakness can be generated in the lab by simply eliminating one CNBP gene copy, thereby rendering them haploinsufficient [3]. Figure 1 depicts the some mice phenotypes found in the wild-type (+/+) and disease (+/-) states.
Another model organism of great value to DM2 research is Drosophila melanogaster or fruit flies. Artero et al. at the University of Valencia successfully created a fruit fly DM2 model by introducing the same tetranucleotide repeats observed in the first intron of the human CNBP gene into flies. These fly model organisms reflect many of the same cellular changes that humans with DM2 experience including toxic CNBP pre-mRNA foci, protein sequestering, and RNA splicing defects. In addition, these genetically modified fruit flies also exhibit detrimental skeletal and cardiac muscle phenotypes consistent with DM2 [4]. Figure 2 depicts the fly phenotypes found in the wild-type (+/+) and disease (+/-) states.
Discussion
The fact that mice have similar musculature to humans and are highly conserved makes them great model organisms for directly observing muscular defects, and even for studying muscle tissue histology. In comparison to fruit flies, however, mice can be more expensive and have longer life spans, so fruit flies are also a great model organism to use when conducting high throughput experiments like chemical screens. While both mice and fruit flies constitute excellent model organisms for studying DM2, they each offer unique advantages when studying this disease. When studying the effects that low CNBP levels can have on the cell, mice are a much better choice since the protein itself and its downstream interacting proteins are much more conserved with humans than flies. When studying the RNA-gain-of-function mechanism, however, flies are a better choice because they are much cheaper and can reliably replicate the mutant CNBP pre-mRNA transcripts.
References
- What are model organisms? (2017, March 03). Retrieved March 16, 2018, from https://www.yourgenome.org/facts/what-are-model-organisms
- Melina, R. (2010, November 16). Why Do Medical Researchers Use Mice? Retrieved March 16, 2018, from https://www.livescience.com/32860-why-do-medical-researchers-use-mice.html
- Cerro-Herreros, E., Chakraborty, M., Pérez-Alonso, M., Artero, R., & Llamusí, B. (2017). Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes. Scientific Reports, 7(1). doi:10.1038/s41598-017-02829-3
- Chen, W., Wang, Y., Abe, Y., Cheney, L., Udd, B., & Li, Y. (2007). Haploinsuffciency for Znf9 in Znf9 /− Mice Is Associated with Multiorgan Abnormalities Resembling Myotonic Dystrophy. Journal of Molecular Biology, 368(1), 8-17. doi:10.1016/j.jmb.2007.01.088
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