GTF2IRD1 regulates cone gene expression to maintain the topology and function of retinal cone photoreceptors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE54164 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA235343
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.
2018-04-20 | E-MTAB-6057 | biostudies-arrayexpress
Project description:Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl in mice (Nrl-/-) results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl-/- retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinned but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of stress response and inflammation genes, implying their involvement in cone death. The Nrl-/- retina illustrates the long-term viability of cones in the absence of rods and may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula. Targets were generated from a pair of retinas (one Nrl-/- mouse) per biological replicate. Four biological replicates were generated for each of the five aging timepoints (1, 2, 4, 6, and 10 months post natal).
2011-11-15 | E-GEOD-33674 | biostudies-arrayexpress
Project description:Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl in mice (Nrl-/-) results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl-/- retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinned but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of stress response and inflammation genes, implying their involvement in cone death. The Nrl-/- retina illustrates the long-term viability of cones in the absence of rods and may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula.
2011-11-15 | GSE33674 | GEO
Project description:The exclusive expression of single sensory receptors in individual neurons (the ‘one-neuron-one receptor’ rule) is essential for vision and other sensory systems. Here, we show that the transcriptional corepressor Samd7 enforces this rule in vertebrate red cones and acts in other photoreceptor types to maintain cell identity. In the zebrafish samd7-/- retina, red cones are transformed to hybrid red/UV-sensitive cones, green cones are transfated to blue cones, and the number of rods is greatly reduced. In the mouse Samd7-/- retina, dorsal M-cones are transformed to hybrid M/S-cones—analogous to the transformation of red to red/UV cones that occurs in zebrafish—and rods aberrantly express cone genes including S-opsin. Altogether, Samd7 acts to repress short-wavelength cone gene expression in long-wavelength-sensitive cones, thereby sustaining the mutually exclusive patterns of opsin expression and cone identity required for color vision.
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Project description:The exclusive expression of single sensory receptors in individual neurons (the ‘one-neuron-one receptor’ rule) is essential for vision and other sensory systems. Here, we show that the transcriptional corepressor Samd7 enforces this rule in vertebrate red cones and acts in other photoreceptor types to maintain cell identity. In the zebrafish samd7-/- retina, red cones are transformed to hybrid red/UV-sensitive cones, green cones are transfated to blue cones, and the number of rods is greatly reduced. In the mouse Samd7-/- retina, dorsal M-cones are transformed to hybrid M/S-cones—analogous to the transformation of red to red/UV cones that occurs in zebrafish—and rods aberrantly express cone genes including S-opsin. Altogether, Samd7 acts to repress short-wavelength cone gene expression in long-wavelength-sensitive cones, thereby sustaining the mutually exclusive patterns of opsin expression and cone identity required for color vision.
2024-06-21 | GSE249755 | GEO
Project description:The exclusive expression of single sensory receptors in individual neurons (the ‘one-neuron-one receptor’ rule) is essential for vision and other sensory systems. Here, we show that the transcriptional corepressor Samd7 enforces this rule in vertebrate red cones and acts in other photoreceptor types to maintain cell identity. In the zebrafish samd7-/- retina, red cones are transformed to hybrid red/UV-sensitive cones, green cones are transfated to blue cones, and the number of rods is greatly reduced. In the mouse Samd7-/- retina, dorsal M-cones are transformed to hybrid M/S-cones—analogous to the transformation of red to red/UV cones that occurs in zebrafish—and rods aberrantly express cone genes including S-opsin. Altogether, Samd7 acts to repress short-wavelength cone gene expression in long-wavelength-sensitive cones, thereby sustaining the mutually exclusive patterns of opsin expression and cone identity required for color vision.
2024-06-21 | GSE249754 | GEO
Project description:The exclusive expression of single sensory receptors in individual neurons (the ‘one-neuron-one receptor’ rule) is essential for vision and other sensory systems. Here, we show that the transcriptional corepressor Samd7 enforces this rule in vertebrate red cones and acts in other photoreceptor types to maintain cell identity. In the zebrafish samd7-/- retina, red cones are transformed to hybrid red/UV-sensitive cones, green cones are transfated to blue cones, and the number of rods is greatly reduced. In the mouse Samd7-/- retina, dorsal M-cones are transformed to hybrid M/S-cones—analogous to the transformation of red to red/UV cones that occurs in zebrafish—and rods aberrantly express cone genes including S-opsin. Altogether, Samd7 acts to repress short-wavelength cone gene expression in long-wavelength-sensitive cones, thereby sustaining the mutually exclusive patterns of opsin expression and cone identity required for color vision.
2024-06-21 | GSE249751 | GEO
Project description:Transcription factors have been implicated in the specification and differentiation of all cells in the mammalian retina with several transcription factors controlling the development of multiple neuronal subclasses. Horizontal cells and cone photoreceptors share a particularly intimate functional relationship but have been previously thought to develop through separate and distinct intrinsic molecular processes. We demonstrate that the zinc finger transcription factor Sall3 regulates development of both S-cone photoreceptors and horizontal cells. Our data shows that loss of function of Sall3 down-regulates the horizontal cell specific transcription factor Lhx1 and subsequently causes ectopic formation of horizontal-like wide-field amacrine cells partially phenocopying Lhx1-/- mice. Additionally, horizontal cells which laminate appropriately in Sall3 knockout mice show abnormal horizontal cell gene expression and failures in dendritic arborization. Over-expression of Sall3 also partially re-specifies cells to a horizontal-like wide-field amacrine fate. Intriguingly, Sall3 loss of function experiments also generated a massive reduction in the number of S-cone photoreceptors with remaining S-cones showing deficiencies in S-cone gene expression and morphology. Conversely, over-expression of Sall3 resulted in the ectopic expression of the S-cone specific genes S-opsin (Sop) and cone arrestin (Arr3) in electroporated cells. Our studies reveal that Sall3 regulates aspects of horizontal cell development in two ways: first, by maintaining Lhx1 expression, and second, by directly regulating expression of horizontal cell specific genes. We also show that Sall3 is an essential regulator of S-cone development in the mammalian retina and a potent activator of Sop and Arr3.
2011-09-10 | GSE24083 | GEO
Project description:Transcription factors have been implicated in the specification and differentiation of all cells in the mammalian retina with several transcription factors controlling the development of multiple neuronal subclasses. Horizontal cells and cone photoreceptors share a particularly intimate functional relationship but have been previously thought to develop through separate and distinct intrinsic molecular processes. We demonstrate that the zinc finger transcription factor Sall3 regulates development of both S-cone photoreceptors and horizontal cells. Our data shows that loss of function of Sall3 down-regulates the horizontal cell specific transcription factor Lhx1 and subsequently causes ectopic formation of horizontal-like wide-field amacrine cells partially phenocopying Lhx1-/- mice. Additionally, horizontal cells which laminate appropriately in Sall3 knockout mice show abnormal horizontal cell gene expression and failures in dendritic arborization. Over-expression of Sall3 also partially re-specifies cells to a horizontal-like wide-field amacrine fate. Intriguingly, Sall3 loss of function experiments also generated a massive reduction in the number of S-cone photoreceptors with remaining S-cones showing deficiencies in S-cone gene expression and morphology. Conversely, over-expression of Sall3 resulted in the ectopic expression of the S-cone specific genes S-opsin (Sop) and cone arrestin (Arr3) in electroporated cells. Our studies reveal that Sall3 regulates aspects of horizontal cell development in two ways: first, by maintaining Lhx1 expression, and second, by directly regulating expression of horizontal cell specific genes. We also show that Sall3 is an essential regulator of S-cone development in the mammalian retina and a potent activator of Sop and Arr3. Sall3 wild-type and knockout retinas used for explant cultures were extracted by microdissection at P0 in sterile PBS. Four cuts were made using micro-dissection scissors and the retinas were transferred to Nucleopore Track-Etch membrane filters (Whatman) and the tissue flattened out evenly. Filters were then floated on DMEM/F12, 10% FBS, 1X penicillin/streptomycin in 12 well plates and incubated at 37oC, 5% CO2 for 7 days. Three retinas (Sall3 knockout or wild-type) were pooled and RNA extracted using the Qiagen RNeasy kit. This was performed in triplicate for both wild-type and Sall3 knockouts retinas. A total of three replicates of Sall3 knockout and Sall3 wild-type RNA were analysed (six total samples).
2011-09-09 | E-GEOD-24083 | biostudies-arrayexpress
Project description:Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from an improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal disease. Here we utilized human organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
2020-01-15 | GSE143669 | GEO