Abstract
Spinal Muscular Atrophy is a recessive genetic disease and affects lower motor neurones and muscle tissue. A single gene is disrupted in SMA: SMN1 activity is abolished but a second copy of the gene (SMN2) provides limited activity. While the SMN protein has been shown to function in the assembly of RNA-protein complexes, it is unclear how the overall reduction in SMN activity specifically results in the neuromuscular phenotypes. Similar to humans, reduced smn activity in the fly causes earliest phenotypes in neuromuscular tissues. To uncover the effects of reduced SMN activity, we have studied gene expression in control and diseased fly tissues using whole genome micro-arrays. A number of gene expression changes are recovered and independently validated. Identified genes show trends in their predicted function: several are consistent with the function of SMN, in addition some uncover novel pathways. This and subsequent genetic analysis in the fly indicates some of the identified genes could be taken for further studies as potential drug targets for SMA and other neuromuscular disorders.
Highlights
Whole genome expression analysis of animals and tissues offers a novel way of penetrating functional changes in diseased versus normal tissues
In order to assess gene expression using micro arrays based on the high density GeneChip system, we needed to establish if it was possible to obtain reliable expression data using small quantities of Drosophila RNA
To assess the validity of our hybridisation results we examined the expression of a number of genes, randomly picked from our list, of differentially expressed genes using Real Time Polymerase Chain Reaction (RT-polymerase chain reaction (PCR)) amplification
Summary
Whole genome expression analysis of animals and tissues offers a novel way of penetrating functional changes in diseased versus normal tissues Such analysis will map direct and indirect effects of the disease state on gene expression and could identify novel gene targets for drug interference. The genome sequencing work and subsequent species comparisons have indicated that the genetic differences between species are smaller than anticipated Both the total number of genes identified and, interestingly, the variety of encoded proteins (and domains) are smaller than expected. Combining these findings with functional genetic analysis has led to the conclusion that for most tissues a group of highly conserved genes is required for differentiation and subsequent function. Tissue specific analysis can be performed in analogous tissues using a wide variety of model organisms, concentrating on these highly conserved genes
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