RETSCOPE : A BIO–INFORMATIC ANALYSIS OF GENE EXPRESSION IN THE DEGENERATIVE RETINA OF THE rd1 MOUSE, A MODEL OF RETINITIS PIGMENTOSA

Abstract

Abstract: : Purpose:We have applied a functional genomic approach to identify potential targets for a rational based therapy of Retinitis Pigmentosa by analyzing the kinetics of rod degeneration of the rd1 mouse. Methods: RNA purified from neural retina of the rd1 and wild–type mice at post–natal (PN) 1 to 35 days corresponding to rod degeneration were hybridized to Affymetrix Genechips®. Gene expression was clustered using density point clustering (Wicker et al., 2002) that generates mean profiles out of 37,000 probes tested. Results: 7 mean profiles were generated. A statistical evaluation of these clusters revealed that six of them represent differences in expression between the two strains of mice and four of them represent differences that can be attributed to photoreceptor degeneration. An extensive bio–informatic analysis was performed on these four clusters using a new bio–informatic platform, RETSCOPE. A multiple alignment approach was used to predicted function and ontologies encoded by the probe sequences. Conclusions:Our analysis provides kinetics as well as spatial knowledge of gene expression during rod degeneration. A wave of transcription is triggered at PN8 in rods by the Pde6b mutation. At PN9, resulting from the transcription and/or directly through the enzymatic deficit, a defect in the establishment of synaptic connection between outer and inner retina is creating an equivalent of the lack of trophic support. Through these mechanisms of amplification, the death of rods starts at PN10 as followed by the decrease in expression of rod specific phototransduction genes. Immediately after, at PN10/11, the inner cells of the retina (e.g. the Müller cells) start to respond to the stress by increasing the expression of endogenous neuroprotective genes.

Keywords: retinal degenerations: hereditary • gene microarray • photoreceptors