Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

Masuda, Tomohiro; Wahlin, Karl; Wan, Jun; Hu, Jianfei; Maruotti, Julien; Yang, Xue; Iacovelli, Jared; Wolkow, Natalie; Kist, Ralf; Dunaief, Joshua L.; Qian, Jiang; Zack, Donald J.; Esumi, Noriko

doi:10.1074/jbc.m114.556738

Cited by 59 publications

(70 citation statements)

References 68 publications

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“…OTX2 regulates RPE genes that are crucially involved in homeostasis and notably the RPE part of the visual cycle (Housset et al ., ; Masuda et al ., ). We next analyzed the expression of TTR and RDH5, both essential for the visual cycle (Cavallaro et al ., ; Yamamoto et al ., ; Cideciyan et al ., ), and TRF, an iron transport protein (He et al ., ; Picard et al ., ).…”

Section: Resultsmentioning

confidence: 97%

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

et al. 2016

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SummaryOrthodenticle homeobox 2 (OTX2) controls essential, homeostatic retinal pigment epithelial (RPE) genes in the adult. Using cocultures of human CD14+ blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human‐induced pluripotent stem cell‐derived RPE cells, we show that activated Mos markedly inhibit RPE OTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF‐α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others. Our data show how subretinal, chronic inflammation and in particular TNF‐α can affect RPE function, which might contribute to the visual dysfunctions in diseases such as age‐related macular degeneration (AMD) where subretinal macrophages are observed. Our findings provide important mechanistic insights into the regulation of OTX2 under inflammatory conditions. Therapeutic restoration of OTX2 expression might help revive RPE and visual function in retinal diseases such as AMD.

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Section: Resultsmentioning

confidence: 97%

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

et al. 2016

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“…Localization at the apical surface of the neuroepithelium (diencephalon and RPE) was also evident. Some retinal and RPE cells expressing Yap also expressed Sox9, a gene essential for RPE and retina development (Masuda et al, 2014; Poche et al, 2008; Zhu et al, 2013). At OC stages, Yap was expressed in most developing ocular tissues of the OC, lens, retina, CB and iris primordia, RPE, cornea, extraocular muscles and periocular mesenchymal cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye

Kim

Park

Lee

et al. 2016

Developmental Biology

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Yap functions as a transcriptional regulator by acting together with sequence-specific DNA binding factors and transcription cofactors to mediate cell proliferation in developing epithelial tissues and tumors. An upstream kinase cascade controls nuclear localization and function in response to partially identified exogenous signals, including cell-to-cell contact. Nevertheless, its role in CNS development is poorly understood. In order to investigate Yap function in developing CNS, we characterized the cellular outcomes after selective Yap gene ablation in developing ocular tissues. When Yap was lost, presumptive retinal pigment epithelium acquired anatomical and molecular characteristics resembling those of the retinal epithelium rather than of RPE, including loss of pigmentation, pseudostratified epithelial morphology and ectopic induction of markers for retinal progenitor cells, like Chx10, and neurons, like β-Tubulin III. In addition, developing retina showed signs of progressive degeneration, including laminar folding, thinning and cell loss, which resulted from multiple defects in cell proliferation and survival, and in junction integrity. Furthermore, Yap-deficient retinal progenitors displayed decreased S-phase cells and altered cell cycle progression. Altogether, our studies not only illustrate the canonical function of Yap in promoting the proliferation of progenitors, but also shed new light on its evolutionarily conserved, instructive role in regional specification, maintenance of junctional integrity and precise regulation of cell proliferation during neuroepithelial development.

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“…8). Moreover, the expression of the three transcription factors (Sox9, Lhx2 and Otx2) that were recently documented to regulate the visual cycle genes (Masuda et al, 2014) was maintained in the Dicer1-deficient RPE (Fig. 2).…”

Section: Dicer1 Is Dispensable For Rpe Fate and Survival During Develmentioning

confidence: 99%

“…2C) and Sox9 detected by antibody labeling (Fig. 2D-E′) (Martinez-Morales et al, 2004;Masuda and Esumi, 2010;Masuda et al, 2014;Nguyen and Arnheiter, 2000). In addition, we did not detect upregulation of Chx10 (Vsx2 -Mouse Genome Informatics), an early expressed retinal transcription factor, indicating that the RPE was not transdifferentiating into neural retinal cells in the Dicer-deficient RPE (Fig.…”

Section: Conditional Ablation Of Dicer1 From Rpe Cells As a Global Inmentioning

confidence: 99%

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

et al. 2015

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Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many proteincoding genes are known to be expressed in RPE and are important for its development and maintenance, virtually nothing is known about the in vivo roles of non-coding transcripts. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and a few were implicated to play role in RPE based on studies in cell lines. Here, through RPE-specific conditional mutagenesis of Dicer1 or Dgcr8 in mice, the importance of miRNAs for RPE differentiation was uncovered. miRNAs were found to be dispensable for maintaining RPE fate and survival, and yet they are essential for the acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly, miRNAs of the RPE are required for maturation of adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The alterations in the miRNA and mRNA profiles in the Dicer1-deficient RPE point to a key role of miR-204 in regulation of the RPE differentiation program in vivo and uncover the importance of additional novel RPE miRNAs. This study reveals the combined regulatory activity of miRNAs that is required for RPE differentiation and for the development of the adjacent neuroretina.

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Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

Cited by 59 publications

References 68 publications

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

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