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Ruth E. Swiderski, Darryl Y. Nishimura, Robert F. Mullins, Marissa A. Olvera, Jean L. Ross, Jian Huang, Edwin M. Stone, Val C. Sheffield; Gene Expression Analysis of Photoreceptor Cell Loss in Bbs4-Knockout Mice Reveals an Early Stress Gene Response and Photoreceptor Cell Damage. Invest. Ophthalmol. Vis. Sci. 2007;48(7):3329-3340. doi: https://doi.org/10.1167/iovs.06-1477.
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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-month-old 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.
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