RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice

Schouwey, Karine; Aydin, Iraz T.; Radtke, Freddy; Beermann, Friedrich

doi:10.1038/onc.2010.428

Cited by 33 publications

(31 citation statements)

References 76 publications

(85 reference statements)

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“…We still know very little about the mechanisms controlling RPE tissue expansion, but some factors and pathways have been implicated including the cyclin-dependent kinase inhibitor protein p27Kip1, the Adenomatous Polyposis Coli (APC) gene, the the tetraspanin protein CD81 and as in many developing tissues, Notch signaling (Defoe et al, 2007; Liou et al, 2004; Marcus et al, 1997; Marcus et al, 2000; Pan et al, 2011; Yoshida et al, 2004)(Schouwey et al, 2011). Genetic inactivation of the Notch effector gene Rbpj in mice causes RPE hypoplasticity and the eyes are microphthalmic, and overactivation of the Notch pathway causes RPE hyperplasia and interferes with differentiation (Schouwey et al, 2011).…”

Section: Overview Of Early Eye Development and Rpe Specificationmentioning

confidence: 99%

“…Genetic inactivation of the Notch effector gene Rbpj in mice causes RPE hypoplasticity and the eyes are microphthalmic, and overactivation of the Notch pathway causes RPE hyperplasia and interferes with differentiation (Schouwey et al, 2011). However, sustained Notch pathway activation does not lead to transdifferentiation into retina.…”

Section: Overview Of Early Eye Development and Rpe Specificationmentioning

confidence: 99%

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Retinal pigment epithelium development, plasticity, and tissue homeostasis

Fuhrmann

Zou

Levine

2014

Experimental Eye Research

206

162

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The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation.

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Section: Overview Of Early Eye Development and Rpe Specificationmentioning

confidence: 99%

Section: Overview Of Early Eye Development and Rpe Specificationmentioning

confidence: 99%

Retinal pigment epithelium development, plasticity, and tissue homeostasis

Fuhrmann

Zou

Levine

2014

Experimental Eye Research

206

162

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“…The Notch pathway controls diverse processes such as stem cell self-renewal, differentiation, and cell fate decisions in many organs, including pigmented and nonpigmented cells in the eye (16–18). Signaling is initiated by the interaction of cell surface Jagged and Delta ligands with Notch receptors on adjacent cells, which activates the pathway through several successive proteolytic cleavages (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

Notch Signaling Promotes Growth and Invasion in Uveal Melanoma

Asnaghi

Ebrahimi

Schreck

et al. 2012

Clinical Cancer Research

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Purpose To determine whether uveal melanoma, the most common primary intraocular malignancy in adults, requires Notch activity for growth and metastasis. Experimental Design Expression of Notch pathway members was characterized in primary tumor samples and in cell lines, along with the effects of Notch inhibition or activation on tumor growth and invasion. Results Notch receptors, ligands, and targets were expressed in all five cell lines examined and in 30 primary uveal melanoma samples. Interestingly, the three lines with high levels of baseline pathway activity (OCM1, OCM3, and OCM8) had their growth reduced by pharmacologic Notch blockade using the γ-secretase inhibitor (GSI) MRK003. In contrast, two uveal melanoma lines (Mel285 and Mel290) with very low expression of Notch targets were insensitive to the GSI. Constitutively active forms of Notch1 and Notch2 promoted growth of uveal melanoma cultures and were able to rescue the inhibitory effects of GSI. MRK003 treatment also inhibited anchorage-independent clonogenic growth and cell invasion and reduced phosphorylation levels of STAT3 and extracellular signal-regulated kinase (Erk)1/2. Suppression of canonical Notch activity using short hairpin RNA targeting Notch2 or CBF1 was also able to reduce tumor growth and invasion. Finally, intraocular xenograft growth was significantly decreased by GSI treatment. Conclusion Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis.

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“…In vitro, enhanced Notch signal by ectopic Dll4 overexpression in the retinal-choroidal EC line RF/6A reduces cell proliferation, migration and transmigration across a monolayer of RPE cells (78). In addition to ECs, RPE cells may be another target of the Notch signal in CNV, because the Notch signal is of importance in RPE development, and constitutive Notch activity leads to RPE hyperproliferation (79). Altogether, these data suggest that Notch signaling is a key regulator of CNV and may be an alternative target for therapeutic intervention in wet AMD.…”

Section: Notch Signaling In Ocular Vascular Diseasesmentioning

confidence: 99%

Notch Signaling in Ocular Vasculature Development and Diseases

Dou

Wang

et al. 2011

Mol Med

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Ocular angiogenesis, characterized by the formation of new blood vessels in the avascular area in eyes, is a highly coordinated process involved in retinal vasculature formation and several ocular diseases such as age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. This process is orchestrated by complicated cellular interactions and vascular growth factors, during which endothelial cells acquire heterogeneous phenotypes and distinct cellular destinations. To date, while the vascular endothelial growth factor has been identified as the most critical angiogenic agent with a remarkable therapeutic value, the Notch signaling pathway appears to be a similarly important regulator in several angiogenic steps. Recent progress has highlighted the involvement, mechanisms and therapeutic potential of Notch signaling in retinal vasculature development and pathological angiogenesis-related eye disorders, which may cause irreversible blindness.

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RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice

Cited by 33 publications

References 76 publications

Retinal pigment epithelium development, plasticity, and tissue homeostasis

Retinal pigment epithelium development, plasticity, and tissue homeostasis

Notch Signaling Promotes Growth and Invasion in Uveal Melanoma

Notch Signaling in Ocular Vasculature Development and Diseases

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