Abstract
Exposure to light can induce photoreceptor cell death and exacerbate retinal degeneration. In this study, mice with genetic knockout of several genes, including rhodopsin kinase (Rhok-/-), arrestin (Sag-/-), transducin (Gnat1-/-), c-Fos (c-Fos-/-) and arrestin/transducin (Sag-/-/Gnat1-/-), were examined. We measured the expression levels of thousands of genes in order to investigate their roles in phototransduction signaling in light-induced retinal degeneration using DNA microarray technology and then further explored the gene network using pathway analysis tools. Several cascades of gene components were induced or inhibited as a result of corresponding gene knockout under specific light conditions. Transducin deletion blocked the apoptotic signaling induced by exposure to low light conditions, and it did not require c-Fos/AP-1. Deletion of c-Fos blocked the apoptotic signaling induced by exposure to high intensity light. In the present study, we identified many gene transcripts that are essential for the initiation of light-induced rod degeneration and proposed several important networks that are involved in pro- and anti-apoptotic signaling. We also demonstrated the different cascades of gene components that participate in apoptotic signaling under specific light conditions.
Highlights
Apoptosis is the final common pathway in many cases of retinal degeneration or retinal disorders, such as retinitis pigmentosa (RP), and these disorders might be ameliorated by interfering with this process (Chang et al, 1993; Portera-Cailliau et al, 1994)
Rod outer segments (ROS) and rod inner segments (RIS) were disorganized, the outer nuclear layer (ONL) was thinner, and pyknotic bodies were seen in Sag-/- mice exposed to 2,000 lux for 24 h
RIS were disorganized, and the ONL became thin in Sag-/, Gnat1-/- or Sag-/-/Gnat1-/- mice exposed to 6,000 lux for 80 min and dark adaptation for 24 h (Figure 1J, L and O), indicating that the strong induction of apoptotic signaling by exposure to high intensity light (6,000 lux) started before 80 min, albeit with a delayed kinetics in the knockouts
Summary
Apoptosis is the final common pathway in many cases of retinal degeneration or retinal disorders, such as retinitis pigmentosa (RP), and these disorders might be ameliorated by interfering with this process (Chang et al, 1993; Portera-Cailliau et al, 1994). Retinal degeneration and its associated signaling networks have attracted much research interest for many years. Several reports have shown that light induces apoptosis in the retina and that components of AP-1 are involved in this process (Hafezi et al, 1997; Hao et al, 2002). The signaling networks that initiate the retinal degeneration cascade are not fully understood. There was an abrogation of signaling from light-activated rhodopsin (Calvert et al, 2000). Light activates rhodopsin, which is phosphorylated by rhodopsin kinase and the signal is terminated by arrestin, which binds with phosphorylated rhodopsin (Dolph, 2002; Miller and Lefkowitz, 2001)
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