Furthermore, the photoreceptor cells displayed extensive ER membrane accumulations and dilated Golgi ( Figure 7A), consistent with aggregation of TRP and Rh1 in the secretory pathway. At 2 weeks, the xport1 mutant photoreceptor cells were severely degenerated. The rhabdomeres of all eight

photoreceptors were vastly reduced and many were completely missing ( Figures 6C and 6D). To assess whether the retinal degeneration was enhanced by light stimulation of phototransduction, we reared the xport1 mutant for 2 weeks in constant darkness. Dark-reared flies still showed ER membrane accumulations and dilated Golgi ( Figure 7D), but now exhibited nearly normal rhabdomere morphology ( Figure 6E). Therefore activation of phototransduction by light enhances the retinal degeneration in xport1 buy Screening Library mutants. The retinal pathology was fully rescued by the expression of wild-type XPORT in the xport1 mutant ( Figure 6F). The molecular mechanisms underlying retinal degeneration are diverse and have been well studied in the Drosophila visual system. Two well-characterized mechanisms involve Capmatinib either (1) accumulation of Rh1 in the secretory pathway due to defective folding/trafficking or (2) unregulated Ca2+ levels due to defective phototransduction ( Colley, 2010, Rosenbaum et al., 2006 and Wang and Montell, 2007). The finding that

light significantly enhanced the retinal degeneration in the xport1 mutant is contrasted to other known mutants defective in Rh1 maturation,

for which the retinal degeneration is light-independent ( Colley et al., 1991, Colley et al., 1995, Kurada and O’Tousa, 1995 and Webel Metalloexopeptidase et al., 2000). However, the xport1 mutant is unique in that it displays defects in both protein trafficking and TRP channel function. Loss of TRP channel expression can lead to a retinal degeneration unrelated to protein trafficking ( Wang and Montell, 2007). In this instance, the retinal degeneration is light-dependent and is triggered by defects in calcium influx through the light-sensitive TRP channels. Given that the retinal degeneration in xport1 is light-enhanced, we investigated the relative contribution of protein trafficking defects versus the lack of TRP channel function to the overall retinal degeneration. To accomplish this, we took advantage of two retinal degeneration mutants, ninaE318 and trp343. The ninaE318 mutant exhibited a severe reduction in Rh1 and displayed defects in Rh1 transport through the secretory pathway ( Figures S5A and S5C). However, TRP protein levels were wild-type in ninaE318 ( Figure S5B). Therefore, ninaE318 exhibits a retinal degeneration that is due solely to defects in protein trafficking. In contrast, the trp343 mutant was null for TRP protein ( Figure S5B) but Rh1 levels were wild-type and Rh1 specifically localized to the rhabdomeres ( Figures S5A and S5C).