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Cellular and molecular characterisation of cone photoreceptor migration in normal and degenerate murine retinae

ABSTRACT: Spatiotemporal cues guiding neuronal migration are critical for the proper development of laminated neural structures, including the retina. Cone photoreceptors, a type of retinal neuron responsible for bright light photopic and colour vision, undergo a unique postmitotic, postnatal migration, yet the cellular and molecular mechanisms that initiate this migration process are still poorly understood. In this study, we explored the role of key phototransduction genes, Cnga3 and Pde6c, in postnatal cone migration by examining two mouse models of complete colour vision blindness, Cnga3-/- and Pde6ccpfl1, which have previously been shown to exhibit aberrant cone localization in adult animals. Retinal development was assessed at postnatal days 8, 12, and 16 using immunohistochemistry and confocal imaging. We found that cone migration and cone soma length were significantly affected in the disease models, indicating that these genes are essential for appropriate postnatal cone migration and final positioning. Furthermore, single-cell RNA sequencing from P12 wildtype and diseased cones identified significant changes to genes involved with the cytoskeleton and its regulation. Our findings strongly indicate a connection between the role of phototransduction genes with cytoskeletal function and cone migration in healthy and degenerating cones.

ORGANISM(S): Mus musculus

PROVIDER: GSE288930 | GEO | 2025/02/11

REPOSITORIES: GEO

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Project description:The loss of cone photoreceptor cells, which are critical for optimal daylight vision, have the great impact on vision during retinal degenerations. Retinal differentiation of human induced pluripotent stem cell (hiPSC) sources could provide a renewable source of cone photoreceptors towards developing a cone cell replacement therapy to treat blindness. Demonstration of comparable gene expression profiles between human foetal and stem cell-derived cones at equivalent stages is required to progress the cell transplantation approach into the patient, as it is hypothesised stem cell-derived cones are required to show high levels of developmental recapitulation of the in vivo generated cones. In this study, the AAV2/9.pR2.1.GFP reporter was used to specifically label L/M-opsin cone photoreceptors in human foetal retinal samples, obtained from the MRC-Wellcome Trust Human Developmental Biology Resource, at a range of developmental stages. The L/M-opsin cone population represent the majority cone cell types in the adult human retina and are the only photoreceptors present within the fovea. Using fluorescence activated cell sorting, L/M-opsin GFP+ cones and GFP- retinal populations, alongside total foetal retinal samples containing all retinal cell tytpes, were isolated and processed for bulk RNA sequencing and downstream comparative analysis. Using DESeq2 differential gene expression analyses, statistically significant genes enriched within the GFP+ human foetal LM-opsin cone populations were determined which led to the identification of a cone enriched gene signature of human L/M-opsin cone photoreceptors. The AAV2/9.pR2.1.GFP reporter was applied to hiPSC-derived retinal cultures to isolate and process cone-like cell populations for RNA sequencing using the same strategy developed within the human foetal retina. Applying the cone enriched gene signature to the transcriptome of hiPSC-derived GFP+ samples at equivalent developmental stages revealed some expression similarities in genes found to be enriched within the late foetal L/M-opsin cone photoreceptors. This analysis overall revealed an intermediate stage of cone differentiation was achieved within the hiPSC-derived samples and the comparison to human foetal L/M-opsin gene express profiles suggesting further differentiation of hiPSC-derived sample is required.

Project description:Tikidji-Hamburyan2018 - Rod phototransduction under strong illumination This model is described in the article: Rods progressively escape saturation to drive visual responses in daylight conditions. Tikidji-Hamburyan A, Reinhard K, Storchi R, Dietter J, Seitter H, Davis KE, Idrees S, Mutter M, Walmsley L, Bedford RA, Ueffing M, Ala-Laurila P, Brown TM, Lucas RJ, Münch TA. Nat Commun 2017 Nov; 8(1): 1813 Abstract: Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses. This model is hosted on BioModels Database and identified by: MODEL1710030000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Cellular and molecular characterisation of cone photoreceptor migration in normal and degenerate murine retinae

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