OTX2 represses sister cell fate choices in the developing retina to promote photoreceptor specification

Tegla, Miruna Georgiana Ghinia; Buenaventura, Diego F.; Kim, Diana Y; Thakurdin, Cassandra; Gonzalez, Kevin; Emerson, Mark M.

doi:10.7554/elife.54279

Cited by 41 publications

(37 citation statements)

References 60 publications

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“…Similarly, developing oligodendrocytes expressed genes previously associates with successive stages in oligodendrocyte maturation (Goldman and Kuypers, 2015) as well a variety of other genes that now become candidates for stage-specific markers. A recent study reported on ~5,000 single cell transcriptomes from chick retinas explanted at E1.5-3 and maintained in vitro for two days (Ghinia Tegla et al, 2020). As expected from the early stage, most of their cells appear to be progenitors, which we did not find at later stages.…”

Section: Retinal Developmentcontrasting

confidence: 59%

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A cell atlas of the chick retina based on single-cell transcriptomics

Yamagata

Yan

Sanes

2021

eLife

110

138

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Retinal structure and function have been studied in many vertebrate orders, but molecular characterization has been largely confined to mammals. We used single-cell RNA sequencing (scRNA-seq) to generate a cell atlas of the chick retina. We identified 136 cell types plus 14 positional or developmental intermediates distributed among the six classes conserved across vertebrates – photoreceptor, horizontal, bipolar, amacrine, retinal ganglion, and glial cells. To assess morphology of molecularly defined types, we adapted a method for CRISPR-based integration of reporters into selectively expressed genes. For Müller glia, we found that transcriptionally distinct cells were regionally localized along the anterior-posterior, dorsal-ventral, and central-peripheral retinal axes. We also identified immature photoreceptor, horizontal cell, and oligodendrocyte types that persist into late embryonic stages. Finally, we analyzed relationships among chick, mouse, and primate retinal cell classes and types. Our results provide a foundation for anatomical, physiological, evolutionary, and developmental studies of the avian visual system.

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Section: Retinal Developmentcontrasting

confidence: 59%

“…A recent study reported on ~5000 single-cell transcriptomes from chick retinas explanted at E1.5–3 and maintained in vitro for 2 days ( Ghinia Tegla et al, 2020 ). As expected from the early stage, most of their cells appear to be progenitors, which we did not find at later stages.…”

Section: Discussionmentioning

confidence: 99%

A cell atlas of the chick retina based on single-cell transcriptomics

Yamagata

Yan

Sanes

2021

eLife

110

138

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“…7 A). Additionally, proteomic analysis showed that the expression of Orthodenticle Homeobox 2 (OTX2) and cone-rod homeobox protein (CRX), both important proteins in the regulation of photoreceptor cell differentiation, 41 – 43 increased in CKO mice retinas ( Fig. 7 E).…”

Section: Resultsmentioning

confidence: 99%

EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development

Cao

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose We used a mouse model to explore the role of the endoplasmic reticulum membrane protein complex subunit 3 (EMC3) in mammalian retinal development. Methods The transcription pattern of Emc3 in C57BL/6 mice was analyzed by in situ hybridization. To explore the effects of EMC3 absence on retinal development, the Cre-loxP system was used to generate retina-specific Emc3 in knockout mice (Emc3 flox/flox , Six3-cre + ; CKO). Morphological changes in the retina of E13.5, E17.5, P0.5, and P7 mice were observed via hematoxylin and eosin staining. Immunofluorescence staining was used to assess protein distribution and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to assess apoptosis changes. Proteins were identified and quantified by Western blotting and proteomic analysis. Electroretinogram (ERG), fundus color photography, and optical coherence tomography were performed on 5-week-old mice to evaluate retinal function and structure. Results The Emc3 mRNA was widely distributed in the whole retina during development. Loss of retinal EMC3 led to retinal rosette degeneration with mislocalization of cell junction molecules (β-catenin, N-cadherin, and zonula occludens-1) and polarity molecules (Par3 and PKCζ). Endoplasmic reticulum stress and TUNEL apoptosis signals were present in retinal rosette-forming cells. Although the absence of EMC3 promoted the production of photoreceptor cells, 5-week-old mice lost all visual function and had severe retinal morphological degeneration. Conclusions EMC3 regulates retinal structure by maintaining the polarity of retinal progenitor cells and regulating retinal cell apoptosis.

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“…The predicted Oc1 binding site was very conserved between ThrbCRM1 and Rxrg208 CRMs, with the predicted Otx2 binding site located very close to the predicted Oc1 site in both CRMs. Rxrg expression in cones has been shown to be regulated by Otx2 and the Onecut genes, although it was not investigated regarding whether it was direct 22,23,63 . To assess the necessity of the Otx2 and Oc1 binding sites within the Rxrg208 CRM, we cloned into Stagia3 the region corresponding to the Rxrg208 sequence with or without Oc1 and Otx2 binding sites (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

“…Since Onecut genes are not expressed in cones, and Otx2 is not expressed in HCs, yet mouse KO’s show a role for both factors in cone and HC development 23,24,26 , an early role, perhaps as pioneer factors in RPCs, is supported. As cells exit mitosis to differentiate, the roles of these two TFs may change, and may include some cross-repression 63 , as well as positive auto-regulation.…”

Section: Discussionmentioning

confidence: 99%

Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development

Lonfat

Wang

Lee

et al. 2020

Preprint

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AbstractThe vertebrate retina is a highly organized structure of approximately 110 cell types. Retinal progenitor cells (RPCs) produce these cell types in a temporal order that is highly conserved. While some RPCs produce many cell types, some terminally dividing RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). Here, we compared the transcriptomes and chromatin profiles of such a restricted cone/HC RPC with those of other RPCs. We identified many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. We then showed that Otx2 and Oc1 directly regulate the activity of multiple CRMs genome-wide, including near genes important for cone development, such as Rxrg and Neurod1. In addition, we found that Otx2 regulates itself. These results suggest that Otx2 and Oc1 have a broader role than previously appreciated, and deepen our understanding of retinal development, which may benefit therapies for retinal diseases.

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OTX2 represses sister cell fate choices in the developing retina to promote photoreceptor specification

Cited by 41 publications

References 60 publications

A cell atlas of the chick retina based on single-cell transcriptomics

A cell atlas of the chick retina based on single-cell transcriptomics

EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development

Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development

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