Although the fate of light-induced and hereditary retinal degeneration is photoreceptor death, fundamental differences exist between the upstream events and the downstream pathways. Using rhodopsin and transducin KO mice to shut off the phototransduction signal, Hao et al.
26 demonstrated the presence of at least two independent apoptotic pathways for light-induced photoreceptor degeneration. Low light intensity induced phototransduction-related apoptosis and high light intensity triggered transcription factor AP-1-induced apoptosis. Although the molecular mechanism of BCL-X
L in photoreceptor survival has not been well investigated, BCL-X
L is considered a downstream target of the PI3K-AKT pathway and a cell death/survival checkpoint regulator of mitochondrial dysfunction. In our study, BCL-X
L expression in the photoreceptors was upregulated after WT mice were subjected to a 48-hour period of bright light stress. To determine the functional significance of bright light-induced BCL-X
L upregulation, a genetic approach was used to disrupt the
Bcl-x gene in photoreceptors. Our results demonstrate that the loss of BCL-X
L, a potential photoreceptor death/survival checkpoint regulator, contributed to increased photoreceptor susceptibility to bright light stress. However, the protective effect of BCL-X
L may only be detected in mice with a genetic background resistant to lower light intensity-induced apoptosis. This may account for the discrepancy between our study and the study of Joseph and Li,
11 in which lower light intensity caused a severe loss of the photoreceptor ONL in the mice overexpressing BCL-X
L, suggesting that the photoreceptor degeneration in these mice was likely a consequence of lower light intensity-induced apoptosis that could circumvent the detection of the protective effect of BCL-X
L under more stringent light intensities. Alternatively, BCL-X
L may only exert its protective effect under high light intensities. A similar light intensity did not cause morphologic or functional changes in our mice, indicating that the mechanisms of photoreceptor apoptosis might be different in these two studies. A recent study may provide some mechanistic insights. Donovan et al.
18 demonstrated that pro-apoptotic BCL-2 family proteins were downregulated during postnatal development and were not upregulated under a low light intensity that caused photoreceptor degeneration in the light-sensitive Balb/c mice. Their results suggest that the BCL-X
L may not be needed as a gatekeeper for mitochondria under this low light intensity-induced stress. The difference in genetic backgrounds and mechanisms of light-induced apoptosis may dictate the role of BCL-X
L in photoreceptor survival and our ability to observe its protective effect under light stress.