|Molecular basis of Fragile X Syndrome: genetic modeling in zebrafish
by Robert Richards, 6/1/2008
Fragile X Syndrome exhibits several characteristic symptoms including mental retardation. The disease is caused by a specific genetic mutation. This mutation causes loss of a protein -- FMRP -- which is needed in the brain for normal development. In addition to mental retardation, other symptoms include craniofacial abnormalities, enhanced sensitivity to sensory stimuli and some epileptic and autistic behaviors.
Existing (mouse and fly, Drosophila) genetic models of the disease indicate that the behavioural abnormalities associated with the condition may be due to abnormal connections between neurons, related to abnormal neuron shape. The zebrafish model of Fragile X Syndrome is an important addition to previous models to aid in understanding the molecular basis of the disease. This is because the zebrafish embryo is transparent and develops outside the mother (enabling direct observation of development in living tissues). This model also provides a highly efficient means for drug screening (drugs can be applied directly to the fish water).
We have discovered that, in the zebrafish model of Fragile X, we can recapitulate the neurite defects found in the other model organisms. The zebrafish FMRP-deficient embryos also uniquely present craniofacial defects that appear to model this symptom of the human syndrome. In the mouse model, behavioral abnormalities have been ameliorated by application of a drug (2-methyl-6-(phenylethynyl)-pyridine; MPEP). We have found that applying this drug to our zebrafish model completely rescues the abnormal neurite shape. This shows that the zebrafish embryo model can be used to screen a wider range of therapeutic agents to find potential treatments for Fragile X Syndrome symptoms in humans. Our research may be pivotal in understanding the molecular biology and the subsequent developmental impact of drug treatments of Fragile X. Understanding a drug’s activities and limitations is critical for its use in humans to avoid undesired outcomes.