Zebra fish are the ultimate study model animal for spinal muscular atrophy (SMA) because their translucent bodies let researchers watch them grow and develop. Zebra fish allow scientists to understand genetic processes better, particularly those in the brain and spinal cord of the central nervous system. The genetic structures in zebra fish are very similar to humans; scientists have even mapped the entire zebra fish genome. Scientists can use zebra fish to unlock the mysteries of how some human diseases — including SMA — develop and progress.
Zebra fish (Danio rerio) are a freshwater species of minnows native to Southeast Asia. They are small — only growing to between 2 centimeters and 4 centimeters long — and are often used as a model organism in scientific research. A model organism, or study model, is an animal that is used to study disease development and progression, as well as treatment options. The zebra fish genome is closer to the human genome compared with other model organisms, such as the fruit fly. They’re also more cost-effective to raise and care for than rodents.
Zebra fish are a particularly useful model species when the disease being studied is physiological and has a developmental time course. In other words, they are ideal when the biology of a disease unfolds over time as a part of an organism’s development. Zebra fish embryos grow in transparent eggs, which lets researchers easily watch as the embryo develops. Zebra fish also mature quickly, which shortens experiment time frames and speeds scientific conclusions.
Because scientists know so much about the zebra fish genome, researchers can use sophisticated genetic techniques to unravel the mechanisms underlying various diseases. From heart function to psychological stress to SMA, zebra fish are integral in disease research.
Zebra fish models can help researchers understand the genetics underlying SMA. SMA is a type of genetic disorder known as an autosomal recessive disorder. This means that a person must inherit two copies of the mutated gene — one from each parent (homozygous). In the case of SMA, this mutation is almost always a deletion of the SMN1 gene at exon 7 on chromosome 5.
The SMN1 gene encodes for survival motor neuron (SMN) protein messenger RNA (mRNA). To get SMN protein, you first need mRNA. Without the proper genetics to code for SMN protein, cells in the anterior horn of the spinal cord will begin to degenerate. This degeneration leads to the symptoms of SMA, including deterioration of motor function, muscle weakness, spine curvatures, and other progressive SMA symptoms.
What do zebra fish have to do with this? Scientists are able to make stronger claims about the role genes play in SMA development from data they collect in experiments with zebra fish. Animal models allow for a high degree of control of specific variables within an experiment, such as the presence or lack of the SMN1 gene. This high degree of control over components of the nervous system has led to many important breakthroughs in neuroscience.
Zebra fish models of SMA have also been used to better understand the role of other SMN genes, such as the SMN2 gene, in the development and disease process of SMA. The SMN2 gene also helps produce SMN protein, but to a lesser extent. However, the number of SMN2 gene copy numbers has been shown to be associated with SMN protein levels and SMA symptom severity. In short, the more copies of the SMN2 gene a person has, the better off they will likely be.
Thanks to zebra fish models, we now understand the nature of this relationship better. For instance, in one study, researchers were able to use genetic techniques to replicate a mutated SMN1 gene in a set of zebra fish. Then, they spliced the SMN2 gene into the zebra fish genome, increasing zebra fish survival in the process — and illustrating a link between SMN2 and SMA disease expression.
Zebra fish models have helped researchers understand SMA beyond the roles of the SMN1 and SMN2 genes. Sometimes, a person can have mutations in the SMN1 gene but not develop SMA, regardless of how many SMN2 copies they have. Zebra fish research has shown that increased amounts of a protein known as plastin 3 can protect against SMA. Plastin 3 prevents problems that can occur in the axon, a part of the neuron that is important for cell-to-cell communication. However, later research showed no improvement in SMA severity when plastin 3 mRNA was introduced to mice with SMA.
Further work with zebra fish has shown that reducing a protein called neurocalcin delta can be a protective factor against SMA. This kind of research is important because it may reveal new therapeutic targets for SMA. However, more research is needed in zebra fish, other animal models, and, one day, humans.
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