by Daniela Zarnescu, 2/1/2002
We are employing the fruitfly, Drosophila melanogaster, as a model for discovery of genes in the Fragile X pathway. The past decade has seen a revolution in our understanding of the genetic homology (similarities) between flies and humans. Drosophila is an excellent system for gene discovery because of the economy of the system, the short generation time, and the available molecular and genetic technology.
The fly eye is comprised of about eight hundred facets arranged in such a precise order that it rivals a crystalline array. This precision in structure requires extreme precision in development: any additional or missing cells can be seen as external disruptions ("rough eye phenotypes"; see figure, middle panel). It is therefore easy to detect any mutation that even slightly disrupts essential cellular processes. The sensitivity to mutations of the Drosophila eye give us the means to conduct a genetic screen and identify genes that function in the Fragile X pathway.
We have obtained transgenic flies that overexpress the fly Fragile X gene in the eye (from our collaborator Tom Jongens; University of Pennsylvania). In these flies, eye development is disrupted and a rough eye phenotype can be easily observed (see figure, middle panel) - we call this the parent phenotype (PES). Then we generated flies that carry random mutations in addition to high levels of Fragile X protein in the eye. The principle of our quest is quite simple: if any of the random mutations affects a gene that functions in concert with the Fragile X gene, chances are that the parental rough eye phenotype will be either enhanced or suppressed, depending on the relationship between the two genes. Recently, by generating mutations into virtually every gene in the fly, we were able to identify several genes which alter the expression of the Fragile X gene in the eye (see figure - PES/Su(Fmr1) and PES/En(Fmr1)). We are currently in the process of cloning these genes in the fly. We look forward to uncovering the relationship between these yet unknown genes and the Fragile X syndrome and hope to enhance our understanding of this disease and also of more general issues such as cognition and intelligence.