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Get Support. Feedback Please let us know what you think of our products and services. Give Feedback. Get Information. Share This Special Issue. Dear Colleagues, The macula at the center of the retina of primates contains the fovea in its middle, an area where cone photoreceptors are highly concentrated, with exclusion of the rod.
IRD COUNTS – the impact of inherited retinal degenerations
For example, the OKR seems to be mainly driven by M- and L-cone signals Orger and Baier, , while the tracking of small dots, at least in goldfish, depends mainly on M-cone signals Gehres and Neumeyer, From previous work that has shown fast functional OKR recovery after S-cone ablation even before regeneration and rewiring occur Hagerman et al. Together, behavioral assays along with NTR-mediated ablation of a given cone subtype, could be used to further expand our understanding of these circuits, and the functional consequences of regeneration and rewiring of the different retinal circuits.
Zebrafish forward genetic screens are extremely powerful, and have been successfully used to uncover novel genes that are involved in photoreceptor function and RD Brockerhoff and Fadool, It is likely that any additional screening that relies on alterations in visual behaviors will continue to uncover new genes that affect photoreceptor function or cause RD. As more causes of RD continue to be unveiled, we now understand that there are limited number of converging pathways that eventually lead to photoreceptor degeneration, including: classic apoptosis, oxidation, activation of proteolytic pathways, misbalance in intracellular levels of cGMP and calcium, and epigenetic regulation Trifunovic et al.
With this knowledge, reverse-genetic approaches using CRISPR-mediated gene editing to target previously undescribed components within these pathways are likely to be extremely useful in the future.
degeneration - Wiktionary
Recent studies in zebrafish have already demonstrated that zebrafish can be used as a platform to rapidly perform genetic screens using CRISPR Varshney et al. In addition to genetic screens, similar to what has been done in fin and hair-cell regeneration studies Mathew et al. Similar screens could also be accomplished using behavioral assays, evaluating the recovery of visual function after regeneration. In paradigms of regeneration after extensive damage surgical of pharmacological in adults, the long regeneration times 8—14 weeks and the diversity of cell types that need to be regenerated might present insurmountable hurdles for screens.
While the majority of regeneration studies in zebrafish have focused on regenerating damaged cells, for functional recovery after regeneration, it is imperative that new cells integrate appropriately into their specific retinal circuits. Our current knowledge on how retinal circuits in the outer retina form during development and after regenerations is limited. Studies into these processes suggest that rewiring after regeneration is not a complete recapitulation of development. Second, not all the transcription pathways that are active during development are reactivated during regeneration Veldman et al.
Third, there seems to be more plasticity and a greater capacity for compensation. In adult zebrafish, after pharmacological ablation of bipolar, amacrine and ganglion cells but survival of photoreceptors and their subsequent regeneration, various subtypes of BCs seem to be able to recapitulate the diversity of connectivity that is found in uninjured eyes, but as a population, selectivity for photoreceptors seems to be restored McGinn et al.
Further investigation is required to explain the disagreement between these studies since there are many differences including ablation technique NTR-MTZ vs. Yet, this raises interesting questions: is the capacity for compensation only present in larvae and lost in the adult? It is interesting to note that selectivity is not lost during rewiring, it is just more permissive, and it is very likely that the same molecules that allow recognition between retinal cell types are used in both development and regeneration.
Only a handful of cell-adhesion and synaptic molecules are known to be necessary for the formation of synaptic contacts between photoreceptors and downstream retinal cells Zhang et al. Some of these molecules are key across all photoreceptors, while others are specific to rods Cao et al. To date, the molecular mechanisms involved in the recognition between specific photoreceptor subtypes and their synaptic partners horizontal and bipolar cells are not known.
Any of the genetic screening tools mentioned above could be combined with the NTR-MTZ transgenic lines Table 1 , to target specific cell subtypes and elucidate the mechanisms that enable rewiring.
Research in this front could have a very significant impact in phenotyping vision loss in RD, and to develop manipulations that could ultimately enable rewiring of transplanted or regenerated photoreceptors into proper retinal circuits. During the last decade, advances in the capacity of high-throughput sequencing has allowed to profile the transcriptomes of whole tissues or dissociated single cells. Gene-expression profiling of retinal cells in mice has given great insight in the classification of retinal cells into different and even novel subtypes Macosko et al.
Peripheral Retinal Degenerations
These techniques can be applied in zebrafish, especially using transgenic lines, as has been recently reported for rods Sun et al. RNAseq of zebrafish retinal cells could help unveil the genes that are required for synapse formation between BC and photoreceptors, genes that could be essential to promote rewiring in RD therapies. RNAseq could also be exploited to study the changes in gene expression that occur during degeneration and regeneration.
This could be accomplished by profiling single cells in the most relevant time points after photoreceptor death. This knowledge will also be extremely valuable for the treatment of RD and understanding how to initiate regeneration after RD. Our field is developing a deep understanding on many aspects of RD, including risk factors, underlying genetic causes, molecular pathways that lead to photoreceptor death, and the manipulations that could slow down the progression of the disease. During the last decade, we have made significant progress into revolutionary therapies that could, 1 day, cure blindness.
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Despite all of the research on RD and regeneration, there are still gaps in our current knowledge that limit our capacity to understand certain aspects of RD and hinder our ability to develop therapies. The zebrafish is an advantageous model to fill in these gaps, especially at a mechanistic level. This knowledge has been directly applied into the mouse retina and successfully used to generate new and functional bipolar and amacrine cells Jorstad et al.
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Although studies have been able to stimulate retinal regeneration in mice using manipulations derived from the study of zebrafish retinal regeneration, but we do not yet fully understand the pathways required to regenerate each retinal cell type, or how these pathways are regulated to regenerate specific subpopulations. This leaves us with little leverage on manipulations that could promote integration of new photoreceptors into the surviving retinal circuits. Solving these issues and finding viable therapeutic options for RD will certainly require diverse approaches.
Research in zebrafish is uniquely poised to make additional key contributions into RD, especially on unveiling the molecular mechanisms involved in photoreceptor regeneration and the processes that guide wiring during development and rewiring after regeneration of photoreceptors into retinal circuits.
studevsegbe.gq JA conceived and carried out the literature review research, designed the figures and diagrams, acquired the images, and wrote the article. KK conceived and carried out the literature review research and wrote the article. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Adler, R. Curing blindness with stem cells: hope, reality, and challenges. Antinucci, P. A crystal-clear zebrafish for in vivo imaging. Ariga, J. Multicolor time-lapse imaging of transgenic zebrafish: visualizing retinal stem cells activated by targeted neuronal cell ablation. Barber, A. Repair of the degenerate retina by photoreceptor transplantation. Bernardos, R. Bibliowicz, J. Toward a better understanding of human eye disease insights from the zebrafish, danio rerio.
Borla, M. Prey capture by larval zebrafish: evidence for fine axial motor control.
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Brain Behav. Bourne, R. Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis. Lancet Glob.