Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration

  1. Ryoji Amamoto
  2. Grace K Wallick
  3. Constance L Cepko

  • Curated by eLife

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    Evaluation Summary:

    Retinitis pigmentosa (RP) is a heterogeneous condition that leads to photoreceptor cell death and thus to different degree of blindness. The degeneration is often caused by mutations in genes expressed in rods but cones end up degenerating as well, although cones positioned in the periphery of the mouse retina appears to be most resistant. This study investigates the possible reasons of this resilience. Using a number of genetic approaches, the authors show that retinoic acid signaling derived from Muller glial cells located in the periphery of the mouse retina is implicated in local survival of cone photoreceptors in mouse models of RP. They further show that RA signaling is also present in the human peripheral retina and suggests that this may be relevant for future therapeutic strategies. The experimental design is excellent involving both loss- and gain-of-function genetic tools to prove the hypothesis that retinoic acid signaling is crucial for cone photoreceptor survival during Retinitis Pigmentosa in mice. Clinical significance remains to be tested, but otherwise the conclusions drawn from the data are well justified.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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Abstract

Retinitis Pigmentosa (RP) is a progressive, debilitating visual disorder caused by mutations in a diverse set of genes. In both humans with RP and mouse models of RP, rod photoreceptor dysfunction leads to loss of night vision, and is followed by secondary cone photoreceptor dysfunction and degeneration, leading to loss of daylight color vision. A strategy to prevent secondary cone death could provide a general RP therapy to preserve daylight color vision regardless of the underlying mutation. In mouse models of RP, cones in the peripheral retina survive long-term, despite complete rod loss. The mechanism for such peripheral cone survival had not been explored. Here, we found that active retinoic acid (RA) signaling in peripheral Muller glia is necessary for the abnormally long survival of these peripheral cones. RA depletion by conditional knockout of RA synthesis enzymes, or overexpression of an RA degradation enzyme, abrogated the extended survival of peripheral cones. Conversely, constitutive activation of RA signaling in the central retina promoted long-term cone survival. These results indicate that RA signaling mediates the prolonged peripheral cone survival in the rd1 mouse model of retinal degeneration, and provide a basis for a generic strategy for cone survival in the many diseases that lead to loss of cone-mediated vision.

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  1. Version published to 10.7554/elife.76389 on eLife
  2. eLife

    Evaluation Summary:

    Retinitis pigmentosa (RP) is a heterogeneous condition that leads to photoreceptor cell death and thus to different degree of blindness. The degeneration is often caused by mutations in genes expressed in rods but cones end up degenerating as well, although cones positioned in the periphery of the mouse retina appears to be most resistant. This study investigates the possible reasons of this resilience. Using a number of genetic approaches, the authors show that retinoic acid signaling derived from Muller glial cells located in the periphery of the mouse retina is implicated in local survival of cone photoreceptors in mouse models of RP. They further show that RA signaling is also present in the human peripheral retina and suggests that this may be relevant for future therapeutic strategies. The experimental design is excellent involving both loss- and gain-of-function genetic tools to prove the hypothesis that retinoic acid signaling is crucial for cone photoreceptor survival during Retinitis Pigmentosa in mice. Clinical significance remains to be tested, but otherwise the conclusions drawn from the data are well justified.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    This is well conducted and interesting study that uses a number of genetic approaches to show that in mice, Muller glia derived retinoic acid signaling favors cone photoreceptors' survival in a mouse model of RP caused by a mutation in a rod specific gene. The relevance of the findings is however over pushed. Survival of a considerable number of photoreceptors is still observed after inactivation of retinoic acid signaling in the retinal periphery, suggesting that other factors might be involved. This is also suggested by the RNA-seq comparison between central and peripheral retinal cells. Therefore, stating that RA signaling is sufficient for cone survival seems an overstatement. The significance of ALDH1A1 expression in the human retinal periphery is also unclear. In the large majority of human RP cases, rod degeneration starts in the retinal periphery and patients are left with tunnel vision, thus it is unclear whether the role of RA signaling in mouse could be of relevance for humans.

  4. eLife

    Reviewer #2 (Public Review):

    This study aims at understanding cellular mechanisms which determine the selective survival of cone photoreceptors located at the periphery of the retina, using mouse models of Retinitis Pigmentosa, a genetic disease leading to photoreceptor death and progressive blindness. Data from this study shows that Retinoic Acid signaling is necessary and sufficient to promote cone survival and that an asymmetry in the expression pattern of its molecular machinery, which predominates at the retinal periphery, is present in the human retina as well.

    Because retinoic acid acts through a general mechanism, independent from the mutation causing RP, the newly described pathway for cone protection can be exploited to promote cone survival in Retinitis Pigmentosa bypassing the high genetic heterogeneity of this disease. Retinoic Acid can also be used in many diseases leading to the degeneration of cones. These cells are fundamental to human vision, so that rescuing even a fraction of them would be therapeutically very relevant.

  5. eLife

    Reviewer #3 (Public Review):

    The authors investigated a question that has wondered many vision/ophthalmology scientists, but still has remained unaddressed to date - What could explain long-term survival of peripheral cone photoreceptors (which is strongly biased to dorsal retina in mice) in rod degenerative diseases, mainly Retinitis Pigmentosa (RP)? This has a counterpart in clinical settings as isolated peripheral islands of cones are often resistant for degeneration in RP, even if photoreceptors die in other parts of the retina. The authors set out to address the issue by sorting cones and Muller glia cells in center vs. peripheral retina in a commonly used Rd1 mouse model of RP. Differential expression analysis reveals Aldh1a1, a crucial enzyme in retinoic acid (RA) synthesis, be distinctly upregulated in peripheral compared to central retina. Next, the authors use a RA response element (RARE) reporter mouse line to show that high RA activity and cone survival pattern correspond well during retina degeneration (RD). Next, the authors use a sophisticated set of genetic RA gain-of-function and loss-of-function experiments, by several complementary methods, to study if RA signaling is both sufficient and necessary for cone survival, respectively. These experiments proved the causal link between peripheral cone survival and colocalized RA activity in Rd1 mouse retinas. Finally, the authors compare ALDH1A1 expression level in peripheral vs. central retina in five post mortem human retinas and show it to be prominently higher in the periphery, suggesting that RA signaling may play a role in long-term peripheral cone survival in human RP patients.

    The MS is of high interest and could potentially be clinically significant, as many clinical drugs (e.g. isotretinoin, disulfiram) can affect RA signaling. The findings could also lead to novel therapeutic strategies in the treatment of retinal degenerations. The experimental design is excellent and well addresses the questions in place. The MS is relatively concise, well-written and easy to understand. The main issue with MS relates to statistical analysis as authors use parametric analysis without justification. The authors do not state if normal distribution was tested, and if data is skewed, how this was considered in statistics. This issue, however, unlikely affects the main results and conclusions of the MS. Secondly, as the authors had access to precious post mortem human retinas, I am wondering why they settled for a simple quantitative PCR of one target gene. Lastly, the retina research community has collected a comprehensive set of open access retinal transcriptomic database (in GEO), including comparisons of human peripheral vs. central retina. I am wondering why authors did not choose to try correlate their findings with already published data by others.

  6. Version published to 10.1101/2021.12.14.472645v1 on bioRxiv