FGF19 Exhibits Neuroprotective Effects on Adult Mammalian Photoreceptors In Vitro

Siffroi-Fernandez, Sandrine; Felder-Schmittbuhl, Marie-Paule; Khanna, Hemant; Swaroop, Anand

doi:10.1167/iovs.07-1272

Cited by 20 publications

(19 citation statements)

References 52 publications

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“…Control of Nrl expression may also depend on extrinsic signaling factors. Notably, FGF and retinoic acid have been implicated in inducing Nrl expression (42,63). Identification of ROR␤ as a direct transcriptional activator of Nrl and potential involvement of CRX, OTX2, and CREB are consistent with combinatorial and cooperative regulation by intrinsic and extrinsic mechanisms.…”

Section: Discussionmentioning

confidence: 69%

Combinatorial Regulation of Photoreceptor Differentiation Factor, Neural Retina Leucine Zipper Gene Nrl, Revealed by in Vivo Promoter Analysis

Kautzmann

Kim

Felder-Schmittbuhl

et al. 2011

Journal of Biological Chemistry

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Development and homeostasis require stringent spatiotemporal control of gene expression patterns that are established, to a large extent, by combinatorial action of transcription regulatory proteins. The bZIP transcription factor NRL (neural retina leucine zipper) is critical for rod versus cone photoreceptor cell fate choice during retinal development and acts as a molecular switch to produce rods from postmitotic precursors. Loss of Nrl in mouse leads to a cone-only retina, whereas ectopic expression of Nrl in photoreceptor precursors generates rods. To decipher the transcriptional regulatory mechanisms upstream of Nrl, we identified putative cis-control elements in the Nrl promoter/ enhancer region by examining cross-species sequence conservation. Using in vivo transfection of promoter-reporter constructs into the mouse retina, we show that a 0.9-kb sequence upstream of the Nrl transcription initiation site is sufficient to drive reporter gene expression in photoreceptors. We further define a 0.3-kb sequence including a proximal promoter (cluster A1) and an enhancer (cluster B) that can direct rod-specific expression in vivo. Electrophoretic mobility shift assays using mouse retinal nuclear extracts, in combination with specific antibodies, demonstrate the binding of retinoid-related orphan nuclear receptor ␤ (ROR␤), cone rod homeobox, orthodenticle homolog 2, and cyclic AMP response element-binding protein to predicted consensus elements within clusters A and B. Our studies demonstrate Nrl as a direct transcriptional target of ROR␤ and suggest that combinatorial action of multiple regulatory factors modulates the expression of Nrl in developing and mature retina.Generation of cellular diversity and homeostasis are controlled and fine tuned through regulation of gene expression. The expression of eukaryotic genes is largely modulated at cissequences of the core promoter and enhancer elements that bind to transcription initiation complex and trans-acting activator or repressor proteins (1, 2). In addition, protein-protein interactions, posttranslational modifications, epigenetic marks on chromatin, and microRNAs facilitate the expression of tissue or cell type-specific genes (3-5). In developmental regulatory networks, spatiotemporal expression of transcription factors primarily dictates functional specification of distinct cell types (6, 7).The vertebrate neural retina, with its in vivo accessibility and a well defined cell repertoire, serves as an excellent model for investigating the origin and maintenance of cellular diversity. The retina consists of six types of neurons and one type of glia. Rod and cone photoreceptors function as specialized sensory neurons that are responsible for scotopic and photopic vision, respectively. Rod photoreceptors are highly vulnerable to genetic defects and environmental abuse (8) and are needed for cone cell viability (9). Hence, elucidation of genesis and functional maintenance of rod photoreceptors would permit better design of strategies for treatment of retinal and mac...

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Section: Discussionmentioning

confidence: 69%

Combinatorial Regulation of Photoreceptor Differentiation Factor, Neural Retina Leucine Zipper Gene Nrl, Revealed by in Vivo Promoter Analysis

Kautzmann

Kim

Felder-Schmittbuhl

et al. 2011

Journal of Biological Chemistry

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“…The activation of FGF19 signalling contributes to maintaining long‐term proliferation and immortalization of colonic epithelial cells . FGF19 stimulates the proliferation and survival of retinal pigment epithelial cells, which exerts a neuroprotective effect . However, little is known about the role of FGF19 in keratinocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

Yan

et al. 2019

Clin Exp Pharma Physio

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Accumulating evidence has shown that fibroblast growth factor 19 (FGF19) plays an important role in regulating cell proliferation. Psoriasis is characterized by the hyperproliferation of keratinocytes in skin lesions. However, whether FGF19 regulates the proliferation of keratinocytes in psoriasis remains unknown. In this study, we aimed to explore the potential relevance of FGF19 in psoriasis. We found that FGF19 was highly expressed in psoriatic skin from psoriasis patients, as well as keratinocytes that were stimulated with a cocktail of cytokines (M5), which is an in vitro model of psoriasis. Functional experiments demonstrated that FGF19 overexpression promoted the growth and proliferation of keratinocytes, while FGF19 knockdown showed opposite effect. Moreover, we found that FGF19 increased the phosphorylation of glycogen synthase kinase (GSK)‐3β and promoted the expression of β‐catenin and the activation of T cell factor 4 (TCF4) transcriptional activity. Notably, blocking Wnt/β‐catenin signalling by silencing β‐catenin partially reversed FGF19‐mediated promotional effects on keratinocyte proliferation. In addition, FGFR4 inhibition significantly blocked the promotional effect of FGF19 on keratinocyte proliferation and GSK‐3β/β‐catenin/TCF4 signalling. Taken together, our results demonstrated that FGF19 contributes to sustaining the high proliferative ability of keratinocytes through promoting Wnt/GSK‐3β/β‐catenin signalling via FGFR4, highlighting the importance of FGF19 in the pathogenesis of psoriasis. Our study suggests that FGF19 may serve as a novel and potential therapeutic target for psoriasis.

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“…Loss of FGF signaling has been associated with degeneration of photoreceptors in several species (Campochiaro et al, 1996; Fontaine et al, 1998; Green et al, 2001; Hochmann et al, 2012; Kinkl et al, 2001; Qin et al, 2011; Siffroi-Fernandez et al, 2008), thus Pea3/Etv4-group ETS factors may play a conserved role in maintenance of differentiated photoreceptors. In addition, the strong expression of etv1 in the developing lens is also consistent with the well-defined role for FGF signaling during lens development (Robinson, 2006).…”

Section: Discussionmentioning

confidence: 99%

The ETS transcription factor Etv1 mediates FGF signaling to initiate proneural gene expression during Xenopus laevis retinal development

Willardsen

Hutcheson

Moore

et al. 2014

Mechanisms of Development

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Fibroblast growth factor signaling plays a significant role in the developing eye, regulating both patterning and neurogenesis. Members of the Pea3/Etv4-subfamily of ETS-domain transcription factors (Etv1, Etv4, and Etv5) are transcriptional activators that are downstream targets of FGF/MAPK signaling, but whether they are required for eye development is unknown. We show that in the developing Xenopus laevis retina, etv1 is transiently expressed at the onset of retinal neurogenesis. We found that etv1 is not required for eye specification, but is required for the expression of atonal-related proneural bHLH transcription factors, and is also required for retinal neuron differentiation. Using transgenic reporters we show that the distal atoh7 enhancer, which is required for the initiation of atoh7 expression in the Xenopus retina, is responsive to both FGF signaling and etv1 expression. Thus, we conclude that Etv1 acts downstream of FGF signaling to regulate the initiation of neurogenesis in the Xenopus retina.

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FGF19 Exhibits Neuroprotective Effects on Adult Mammalian Photoreceptors In Vitro

Abstract: These data indicate a physiological role for FGF-19 in adult photoreceptor phenotypic maintenance and survival and argue in favor of its use as a neuroprotectant.

Cited by 20 publications

References 52 publications

Combinatorial Regulation of Photoreceptor Differentiation Factor, Neural Retina Leucine Zipper Gene Nrl, Revealed by in Vivo Promoter Analysis

Combinatorial Regulation of Photoreceptor Differentiation Factor, Neural Retina Leucine Zipper Gene Nrl, Revealed by in Vivo Promoter Analysis

FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK‐3β/β‐catenin signalling via FGFR4

The ETS transcription factor Etv1 mediates FGF signaling to initiate proneural gene expression during Xenopus laevis retinal development

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