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Aberrant expression of c-Fos accompanies photoreceptor cell death in the rd mouse
1Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Abstract:
Selective degeneration of rod photoreceptor cells in the retinal degenerative (rd) mouse prior to their complete maturation is thought to result from elevated cyclic guanosine monophosphate (cGMP) levels owing to the inherited defect in cGMP-phosphodiesterase. To investigate potential signaling pathways which might lead to apoptotic death of photoreceptors in the rd retina, the expression of immediate-early genes (IEG) of the activating protein-1 transcription factor (AP-1) family was examined. Increasing numbers of apoptotic photoreceptor nuclei were observed in the outer nuclear layer of the rd mouse beginning at postnatal day (P) 10. The peak incidence of apoptotic cells was observed at P13; by P16, almost the entire population of photoreceptors had been lost. Although c-Fos-like immunoreactivity was absent in photoreceptors of normal retinas, we observed that commencing at around P10, increasing numbers of rod photoreceptors in the rd retina exhibited nuclear staining for c-Fos protein. While no change in the distribution patterns of other members of the AP-1 family (c-Jun, JunB, and JunD) was observed in photoreceptors, Müller cell nuclei were transiently immunoreactive for c-Jun on P11. The incidence of c-Fos-positive photoreceptors peaked sharply at P12, 1 day earlier than the peak in apoptosis. Furthermore, the population of c-Fos-positive photoreceptors was distinct from apoptotic photoreceptors exhibiting chromatin condensation. The aberrant expression of c-Fos protein in rod photoreceptors immediately prior to their death in the rd mouse raises the possibility that c-Fos may be directly or indirectly involved in triggering the apoptotic cascade. Furthermore, the additional finding of c-Jun induction in Müller glia suggests that the IEG response to photoreceptor degeneration involves both intra- and intercellular signal transduction pathways.
Insights
In retinal degenerative mice, aberrant c-Fos protein expression in rod photoreceptors precedes cell death, suggesting a role in apoptosis. Müller glia also show c-Jun induction, indicating complex signaling in photoreceptor degeneration.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Retinal degenerative (rd) mouse model exhibits photoreceptor cell loss due to inherited defects.
- Elevated cyclic guanosine monophosphate (cGMP) is implicated in photoreceptor degeneration in rd mice.
- Investigating signaling pathways is crucial for understanding photoreceptor apoptosis.
Purpose of the Study:
- To examine immediate-early gene (IEG) expression, specifically the activating protein-1 (AP-1) transcription factor family, in the rd mouse retina.
- To identify potential molecular triggers for apoptotic death of photoreceptor cells.
Main Methods:
- Immunohistochemistry was used to detect c-Fos, c-Jun, JunB, and JunD expression in rd and normal mouse retinas.
- Apoptosis was assessed by counting apoptotic photoreceptor nuclei in the outer nuclear layer.
- Temporal expression patterns of IEGs were correlated with the timing of photoreceptor degeneration.
Main Results:
- Photoreceptor apoptosis increased significantly in rd mice from postnatal day 10, peaking at P13 and leading to near-complete loss by P16.
- Aberrant nuclear c-Fos immunoreactivity was detected in rd mouse rod photoreceptors starting around P10, peaking at P12.
- While other AP-1 members showed no change in photoreceptors, Müller cells exhibited transient c-Jun immunoreactivity on P11.
Conclusions:
- Aberrant c-Fos expression in rd mouse rod photoreceptors suggests its potential involvement in initiating the apoptotic cascade.
- The induction of c-Jun in Müller glia indicates that photoreceptor degeneration involves both intracellular and intercellular signaling pathways.
- Understanding these IEG responses provides insights into the complex mechanisms driving retinal degenerative diseases.