Gene Expression Analysis of Photoreceptor Cell Loss in Bbs4-Knockout Mice Reveals an Early Stress Gene Response and Photoreceptor Cell Damage

PURPOSE. To identify and characterize gene expression changes associated with photoreceptor cell loss in a Bbs4-knockout mouse model of retinal degeneration. METHODS. Differential gene expression in the eyes of 5-monthold Bbs4 / mice undergoing retinal degeneration were analyzed using gene microarrays (Affymetrix, Santa Clara, CA). Elevated ocular transcripts were confirmed by Northern blotting of RNA from Bbs4 / and three additional mouse models of Bardet-Biedl Syndrome (BBS). TUNEL assays and transmission electron microscopy were used to study cell death and photoreceptor morphology in these mice. RESULTS. Three hundred fifty-four probes were differentially expressed in Bbs4 / eyes compared with controls using a twofold cutoff. Numerous vision-related transcripts decreased because of photoreceptor cell loss. Increased expression of the stress response genes Edn2, Lcn2, Serpina3n, and Socs3 was noted at 5 months of age and as early as postnatal week 4 in the eyes of four BBS mouse model strains. A burst of apoptotic activity in the photoreceptor outer nuclear layer at postnatal week 2 and highly disorganized outer segments by postnatal weeks 4 to 6 was observed in all four strains. CONCLUSIONS. The specific loss of photoreceptors in Bbs4 / mice allows us to identify a set of genes that are preferentially expressed in photoreceptors compared with other cell types found in the eye and is a valuable resource in the continuing search for genes involved in retinal disease. The molecular and morphologic changes observed in young BBS animal model eyes implies that BBS proteins play a critical, early role in establishing the correct structure and function of photoreceptors. (Invest Ophthalmol Vis Sci. 2007;48: 3329‐3340) DOI:10.1167/iovs.06-1477