Programmed Cell Death During Retinal Development of the Mouse Eye

Braunger, Barbara M.; Demmer, Cora; Tamm, Ernst R.

doi:10.1007/978-1-4614-3209-8_2

Cited by 26 publications

(25 citation statements)

References 22 publications

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“…In Rpe65 +/+ retina, the GFP hi cells in the INL declined by P14 (Fig. 3C; p<0.05), consistent with their activation and association with clearing inner retinal neurons undergoing apoptosis at that time [26]. Onset of cone degeneration in the Rpe65 −/− mice, based on the first appearance of TUNEL + cells in the ONL at P13 [27], overlapped with the end of developmental remodeling in the INL and associated apoptosis in the INL (Fig.…”

Section: Resultsmentioning

confidence: 63%

A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis

Tang

Heuss

Gregerson

2017

Molecular and Cellular Neuroscience

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Background Studies of antigen presentation in retina using mice that expressed green fluorescent protein (GFP) from a transgenic CD11c promoter found that retinal GFPhi cells possessed antigen presentation function. Subsequent studies found that these high GFPhi cells preferentially localized to sites of retinal injury, consistent with their APC function. Interest in the roles of macrophages in degenerative CNS diseases led us to study the GFPhi cells in a retinal model of neurodegeneration. We asked if apoptotic cone photoreceptor cell death in Rpe65−/− knockout mice induced the GFPhi cells, explored their relationship to resident microglia (MG), and tested their role in cone survival. Methods Rpe65−/− mice were bred to CD11cGFP mice on the B6/J background. CD11cGFPRpe65−/− mice were also backcrossed to CX3CR1YFP-creERROSADTA mice so that CX3CR1+ mononuclear cells could be depleted by Tamoxifen. Retinas were analyzed by immunohistochemistry, confocal microscopy, fluorescence fundoscopy and flow cytometry. Results Elevated numbers of GFPhi cells were concentrated in photoreceptor cell layers of CD11cGFPRpe65−/− mice coinciding with the peak of cone death at 2 to 4 weeks of age, and persisted for at least 14 months. After the initial wave of cone loss, a slow progressive loss of cones was found that continued to retain GFPhi cells in the outer retina. Sustained, four-week Tamoxifen depletions of the GFPhi cells and MG in Rpe65−/− mice from day 13 to day 41, and from day 390 to day 420 promoted a small increase in cone survival. We found no evidence that the GFPhi cells were recruited from the circulation; all data pointed to a MG origin. MG and GFPhi cells were well segregated in the dystrophic retina; GFPhi cells were foremost in the photoreceptor cell layer, while MG were concentrated in the inner retina. Conclusions The expression of GFP on a subset of retinal mononuclear cells in CD11cGFP mice identifies a distinct population of cells performing functions previously attributed to MG. Although GFPhi cells dominated the macrophage response to cone death in the photoreceptor cell layer, their ablation led to only an incremental increase in cone survival. The ability to identify, ablate, and isolate these cells will facilitate analysis of this activated, antigen-presenting subset of MG.

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Section: Resultsmentioning

confidence: 63%

A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis

Tang

Heuss

Gregerson

2017

Molecular and Cellular Neuroscience

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“…During eye development, cell death allows for the selection of appropriate synaptic connections (Braunger, Demmer, & Tamm, 2014). Dysregulation of programmed cell death, however, has been linked to the pathogenesis of several retinal diseases, including RD and AMD (Kaarniranta, Tokarz, Koskela, Paterno, & Blasiak, 2017; Torriglia, Jaadane, & Lebon, 2016).…”

Section: Resultsmentioning

confidence: 99%

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

et al. 2018

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Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision‐threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry‐based label‐free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age‐related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.

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“…Caspases are a family of protease enzymes playing essential roles in programmed cell death and infl ammation. During eye development, cell death allows selection of appropriate synaptic connections 53 . Dysregulation of programmed cell death, however, has been linked to the pathogenesis of several retinal diseases, including retinal detachment and AMD 54,55 .…”

Section: Comparison Of Ierm and Mh Proteomesmentioning

confidence: 99%

Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases

Öhman

Tamene

Göös

et al. 2018

Preprint

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Aging is a phenomenon associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases aff ecting millions of aging people globally, making these conditions an important public health issue. The iERM is characterized by fi brous tissue developing on the surface of the macula, leading to biomechanical and biochemical macular damage. MH is a small breakage in the macula associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM (n=26) and MH (n=21) to identify the key proteins as well as the multiple interconnected biochemical pathways contributing to the development of these diseases. We identifi ed a total of 1014 unique proteins, of which many were linked to infl ammation and complement cascade, revealing the infl ammational processes in retinal diseases. Additionally, we detected a profound diff erence in proteomes of the iEMR and MH compared to the non-proliferative diabetic retinopathy. A large number of neuronal proteins were present at higher levels in iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins and signalling molecules. This points toward the important role of neurodegeneration component in the pathogenesis of age-related vitreoretinal diseases. Despite of marked similarities, several unique vitreous proteins were identifi ed in both iERM and MH conditions, providing a candidate targets for diagnostic and new therapeutic approaches. Identifi cation of previously reported and novel proteins in human vitreous humor from patient with iERM and MH provide renewed understanding of the pathogenesis of age-related vitreoretinal diseases.

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Programmed Cell Death During Retinal Development of the Mouse Eye

Cited by 26 publications

References 22 publications

A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis

A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases

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