CRB2 completes a fully expressed Crumbs complex in the Retinal Pigment Epithelium

Paniagua, Antonio E.; Herranz-Martín, Saúl; Jimeno, David; Jimeno, Ángela M.; López-Benito, Saray; Arévalo, Juan Carlos; Velasco, Almudena; Aijón, José; Lillo, Concepción

doi:10.1038/srep14504

Cited by 16 publications

(20 citation statements)

References 59 publications

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“…In the adult mouse RPE, 1st and 2nd trimester human fetal RPE, and human iPSC-derived RPE CRB2 has been found to be expressed [129,276]. In the both human fetal and iPSC-derived RPE CRB2 immuno-EM labeling was found above adherens junctions and tight junctions in the apical membrane and microvilli [129].…”

Section: The Localization Of the Mammalian Retinal Crb Complexmentioning

confidence: 94%

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Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Quinn

Wijnholds

2019

Genes

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The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.

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Section: The Localization Of the Mammalian Retinal Crb Complexmentioning

confidence: 94%

Section: The Localization Of the Mammalian Retinal Crb Complexmentioning

confidence: 96%

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Quinn

Wijnholds

2019

Genes

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“…In this study, the expression of CRB2, one of the three members of the CRB protein family, in adult mouse brain, was investigated. Previous works have shown the expression of CRB1 in brain 16 , but to date there is no data regarding the expression and localization of CRB2 in this tissue; although it has been shown to be present in the mouse brain during embryogenesis 21 , 41 , in the retinal pigment epithelium 20 and in neural retina 42 , 43 . Although previous reports have suggested the presence of CRB2 mRNA in neurons 39 , the lack of evidence supporting this could be due to the absence of proper tools that would have allowed more detailed studies.…”

Section: Discussionmentioning

confidence: 97%

“…CRB2/Crb2 , again through RT-PCR and in situ hybridization analysis, was found in kidney, retinal pigment epithelium and choroid, the adult brain and at low levels in the placenta, heart and lung 18 , 19 . Expression of the CRB2 protein has been shown in the retinal pigment epithelium 20 and in the embryonic mouse brain 21 . Finally, CRB3/Crb3 , the most ubiquitously expressed of the three members, has been described in many diverse epithelial-derived tissues, including the retina 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

Expression and localization of the polarity protein CRB2 in adult mouse brain: a comparison with the CRB1rd8 mutant mouse model

Dolón

Paniagua

Valle

et al. 2018

Sci Rep

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Acquisition of cell polarization is essential for the performance of crucial functions, like a successful secretion and appropriate cell signaling in many tissues, and it depends on the correct functioning of polarity proteins, including the Crumbs complex. The CRB proteins, CRB1, CRB2 and CRB3, identified in mammals, are expressed in epithelial-derived tissues like brain, kidney and retina. CRB2 has a ubiquitous expression and has been detected in embryonic brain tissue; but currently there is no data regarding its localization in the adult brain. In our study, we characterized the presence of CRB2 in adult mice brain, where it is particularly enriched in cortex, hippocampus, hypothalamus and cerebellum. Double immunofluorescence analysis confirmed that CRB2 is a neuron-specific protein, present in both soma and projections where colocalizes with certain populations of exocytic and endocytic vesicles and with other members of the Crumbs complex. Finally, in the cortex of CRB1rd8 mutant mice that contain a mutation in the Crb1 gene generating a truncated CRB1 protein, there is an abnormal increase in the expression levels of the CRB2 protein which suggests a possible compensatory mechanism for the malfunction of CRB1 in this mutant background.

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“…Its most conserved markers were mostly known to be expressed in the RPE (DCT, TTR, CST3, AQP1, FTH1 [27], BEST1), with some markers, such as TFPI2, known to promote survival and maintenance of RPE cells [28]. The markers were similar to those of the "Common" and CRB2 [31], involved in RPE polarity [32], suggests an early stage of RPE maturity. This pattern is suggestive of a differentiating RPE population.…”

Section: Most Cells Share Common Transcriptomic Profiles Suggestive Omentioning

confidence: 97%

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Over Time

Lidgerwood

Senabouth

Smith-Anttila

et al. 2019

Preprint

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We differentiated the human embryonic stem cell line H9 into retinal pigment epithelium (RPE) cells to assess temporal changes in transcriptomic profiles of cells. We performed single cell RNA-Sequencing of a total of 16,576 cells, and analysed the resulting data to access the molecular changes of RPE cells across two culture time points (1 and 12 months). Our results indicate the stability of the RPE transcriptomic signature over time in culture, with results indicating maturing populations of RPE could be observed over time, with no evidence of an epithelial -mesenchymal transition. Assessment of gene ontology (GO) pathways reveals that as cell cultures age, RPE cells upregulate expression of genes involved in metal binding and antioxidant functions, which might reflect an increased ability to handle oxidative stress as cells mature. Comparison with the transcriptional profiles of native RPE identified a progression towards a maturing RPE profile. These results suggest that in vitro long-term culture of RPE cells allow the modelling of phenotypes observed in native mature tissue. Our work highlights the changing transcriptional landscape of hPSC-derived RPE as they age in culture, which provides a reference for native and patient-samples to be benchmarked against.

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CRB2 completes a fully expressed Crumbs complex in the Retinal Pigment Epithelium

Cited by 16 publications

References 59 publications

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Expression and localization of the polarity protein CRB2 in adult mouse brain: a comparison with the CRB1rd8 mutant mouse model

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Over Time

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