Thyroid hormone signaling specifies cone subtypes in human retinal organoids
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PROVIDER: PRJNA488731 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue/S, green/M and red/L cones of the retina enable high-acuity daytime and color vision. To determine the mechanism controlling S vs. L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone-degrading and activating proteins within the retina ensures low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining mechanisms of human development with promising utility for therapeutics and vision repair.
2018-10-12 | GSE119320 | GEO
Project description: Not available
| S-EPMC6249681 | biostudies-literature
Project description:Purpose: To define the cone photoreceptor diversity and underlying transcriptional controls in mouse retina Methods: Individual retinal cone cells were isolated by micro-manipulator from dissociated pieces of superior/inferior retina from heterozygous (or homozygous) Thrb-b2Cre:Ai6 mice. Single cell libraries were constructed for RNA-seq analysis. Thrb-b2Cre;Rosa26-Sun1Gfp mice were used to isolate cone nuclei for ATAC-seq analysis. Thrb-HAB mice were used to identify TRb2 genomic binding sites using ChAP-seq analysis. Results: Developmental analyses of individual cones revealed a network of gradient genes. Many of these gradient genes are regulated by TRb2, a thyroid hormone receptor that has been associated with color visual impairment. Conclusions: The results suggest that TRb2 controls chromatin remodeling and transcriptional plasticity in the cone lineage to promote diversity.
2022-12-05 | GSE203481 | GEO
Project description:Here we reveal a novel role for the circadian clock gene Bmal1 and Period2 in regulating the spatial organization of the cone opsins. Deletion of Bmal1 and Per2 have opposing effects on S-opsin expression and patterning of the cone photoreceptors is disrupted in cone specific knockouts of these genes. Using ChIP analysis we show that BMAL1 directly binds to the promoter region of the thyroid activating enzyme type II deiodinase (Dio2).
2017-10-17 | GSE103484 | GEO
Project description:The mechanisms that specify cone photoreceptor cell-fate to short-wave-sensitive (S) versus medium-wave-sensitive (M) cones and maintain their nature are not fully understood. Here we report the importance of the GTF2IRD1 transcription factor in maintaining M cone cell identity and function. In the mouse, GTF2IRD1 is expressed in cell-fate determined photoreceptors at postnatal day 10. GTF2IRD1 binds to the enhancer and promoter regions of mouse M and S opsin genes, but regulates their expression differentially, suppressing S opsin expression and, through interaction with the transcription factors CRX and TR2, enhancing M opsin expression. Null mutation of Gtf2ird1 leads to altered topology of cone opsin expression in the retina, with aberrant S opsin over-expression and M opsin under-expression in M cones. Gtf2ird1 null mice also demonstrate abnormal M cone electrophysiological responses. These findings indicate a dual and specific regulatory role of GTF2IRD1 in maintaining normal M cone-specific gene expression and function.
2014-12-31 | GSE54164 | 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: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:Purpose: Using customized RNA-sequencing analyses to reveal notably different expression profiles of TRb1 and TRb2 in mouse retina. Method and Results: TRb2 peaks early whereas TRb1 peaks later during retinal maturation or during later differentiation. TRb1-knockout mice displayed only minor changes in opsin photopigment expression and normal electroretinogram responses, indicating that TRb2 and TRb1 are not functionally equivalent in cone differentiation. The biphasic expression patterns of TRb1 and TRb2 suggest versatile functions for thyroid hormone in retinal and non-neural ocular development.
2023-04-18 | GSE224863 | GEO
Project description:The macula of the retina has a high ratio of cones to rods and is critical for central vision and visual acuity. Macula degenerations affect vision the most and are incurable. Here we report the generation, transcriptome profiling, and functional validation of cone-enriched human retinal organoids differentiated from hESCs. Transcriptome profiling using bulk RNA-seq demonstrated that retinal differentiation in vitro recapitulated retinogenesis in vivo in the temporal expression of cell differentiation markers and retinal disease genes, as well as in mRNA alternative splicing. Single-cell RNA-seq of 8-month retinal organoids identified clusters of cone and rod photoreceptors and confirmed the cone enrichment initially revealed by immunostaining. Notably, comparisons of single-cell transcriptomes demonstrated the similarity between retinal organoids and human macula in cones and rods. Cones in retinal organoids exhibited electrophysiological functions. Collectively, we have established cone-enriched retinal organoids and a reference of transcriptomes that are rich resources for retinal studies.
2019-04-25 | GSE119274 | GEO
Project description:Thyroid hormone receptor beta (THRB) is post-translationally modified by small ubiquitin-like modifier (SUMO). To investigate the biological role of THRB sumoylation, we generated a mouse model with a mutation that disrupts sumoylation at lysine 146 (K146Q). The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin (TSH) (81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4 concentration, indicated blunted feedback regulation of TSH. TH profuction was 10-fold lower (per mg of thyroid tissue) in mutant mice compared to Wt mice.
2021-02-20 | GSE167105 | GEO