Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets

Arsenijévic, Yvan

doi:10.1007/978-3-319-17121-0_49

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…We, and other researchers, have observed an age-dependent restriction of MG proliferation in mammals and other species (Fischer, 2005;Loffler et al, 2015), whereas in zebrafish MG more readily proliferate upon injury or experimental stimulation (Goldman, 2014;Lenkowski and Raymond, 2014). Our SAG data suggest that glia, and possibly even neurons, re-enter or activate parts of the cell cycle, which may contribute to neurodegeneration (Robel et al, 2011;Zencak et al, 2013;Arsenijevic, 2016;Sardar Pasha et al, 2017). This SAG model might also facilitate studies on the acquisition and maintenance of cell homeostasis, and glia-derived neuronal regeneration (Loffler et al, 2015;Sardar Pasha et al, 2017;Lahne et al, 2020).…”

Section: Discussionsupporting

confidence: 57%

“…ROCKi, a rho-associated kinase (ROCK) inhibitor, may reduce MG proliferation and gliosis (Tura et al, 2009;Zhang et al, 2015;Halasz et al, 2021). CDK4i blocks cyclindependent kinase 4 (CDK4), and drives cell proliferation and possibly cell death (Arsenijevic, 2016). Inhibitors were applied 7 h before HT, and subsequently added daily together with HT until D25 (Figure 6A, N = 3 independent experiments, n ≥ 10 MROs/N and variable).…”

Section: Pharmacologicals Differentially Prevent Photoreceptor and Gl...mentioning

confidence: 99%

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Modeling inducible neuropathologies of the retina with differential phenotypes in organoids

Völkner

Wagner

Kurth

et al. 2023

Front. Cell. Neurosci.

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Neurodegenerative diseases remain incompletely understood and therapies are needed. Stem cell-derived organoid models facilitate fundamental and translational medicine research. However, to which extent differential neuronal and glial pathologic processes can be reproduced in current systems is still unclear. Here, we tested 16 different chemical, physical, and cell functional manipulations in mouse retina organoids to further explore this. Some of the treatments induce differential phenotypes, indicating that organoids are competent to reproduce distinct pathologic processes. Notably, mouse retina organoids even reproduce a complex pathology phenotype with combined photoreceptor neurodegeneration and glial pathologies upon combined (not single) application of HBEGF and TNF, two factors previously associated with neurodegenerative diseases. Pharmacological inhibitors for MAPK signaling completely prevent photoreceptor and glial pathologies, while inhibitors for Rho/ROCK, NFkB, and CDK4 differentially affect them. In conclusion, mouse retina organoids facilitate reproduction of distinct and complex pathologies, mechanistic access, insights for further organoid optimization, and modeling of differential phenotypes for future applications in fundamental and translational medicine research.

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Section: Discussionsupporting

confidence: 57%

Section: Pharmacologicals Differentially Prevent Photoreceptor and Gl...mentioning

confidence: 99%

Modeling inducible neuropathologies of the retina with differential phenotypes in organoids

Völkner

Wagner

Kurth

et al. 2023

Front. Cell. Neurosci.

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“…Our work exposes new roles for Rb in the developing retina, pinpointing aberrant E2f1 and Bax activity as key drivers of defects in neuronal survival and angiogenesis, and further implicating E2f1 in aberrant lamination. The Rb/E2f pathway is commonly involved in many diseases, such as most human cancers 13 , retinal degeneration 51 , diabetic retinopathy 52 , and neuronal degeneration 53 . Abnormal cell survival, proliferation, angiogenesis, and lamination are common features of these diseases.…”

Section: Discussionmentioning

confidence: 99%

Rb is required for retinal angiogenesis and lamination

et al. 2018

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Retinoblastoma tumor suppressor (Rb) promotes cell cycle exit, survival, differentiation, and tumor suppression in the retina. Here, we show it is also essential for vascularization and lamination. Despite minimal effects on Hif1a target expression, intraretinal vascular plexi did not form in the Rb−/− murine retina. Deleting adenovirus E2 promoter binding factor 3 (E2f3), which rescues starburst amacrine cell differentiation, or E2f2, had no effect, but deleting E2f1, which promotes neuronal cell cycle exit and survival, restored retinal vasculature. We specifically linked cell loss to the defect because removing Bax rescued rod and bipolar neurons and the vasculature, but not cell cycle exit. Despite rescuing Rb−/− neurons, Bax deletion exacerbated a delay in outer retina lamination, and exposed a requirement for Rb in inner retina lamination. The latter resembled Sem5 or FAT atypical cadherin 3 (Fat3) mutants, but expression of Sem5/Fat3 pathway components, or that of Neogenin, which perturbs migration in the Rb−/− cortex, was unchanged. Instead, lamination defects correlated with ectopic division, and were E2f1-dependent, implicating the cell cycle machinery. These in vivo studies expose new developmental roles for Rb, pinpoint aberrant E2f1 and Bax activity in neuronal death and vascular loss, and further implicate E2f1 in defective lamination. Links between Rb, angiogenesis and lamination have implications for the treatment of neovascularization, neurodegeneration and cancer.

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“…29 As EdU also labels cells that are dying or repairing their DNA, these GS ¡ /EdU C cells may also be dying neurons. 30 They were mainly in the GCL and INL (Fig. 2A and B).…”

Section: High Glucose Induced Ectopic Cell Division Of M€ Uller Glial Cells and Neurons In Retinal Explantsmentioning

confidence: 96%

E2f1 mediates high glucose-induced neuronal death in cultured mouse retinal explants

et al. 2017

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Diabetic retinopathy (DR) is the most common complication of diabetes and remains one of the major causes of blindness in the world; infants born to diabetic mothers have higher risk of developing retinopathy of prematurity (ROP). While hyperglycemia is a major risk factor, the molecular and cellular mechanisms underlying DR and diabetic ROP are poorly understood. To explore the consequences of retinal cells under high glucose, we cultured wild type or E2f1 mouse retinal explants from postnatal day 8 with normal glucose, high osmotic or high glucose media. Explants were also incubated with cobalt chloride (CoCl) to mimic the hypoxic condition. We showed that, at 7 days post exposure to high glucose, retinal explants displayed elevated cell death, ectopic cell division and intact retinal vascular plexus. Cell death mainly occurred in excitatory neurons, such as ganglion and bipolar cells, which were also ectopically dividing. Many Müller glial cells reentered the cell cycle; some had irregular morphology or migrated to other layers. High glucose inhibited the hyperoxia-induced blood vessel regression of retinal explants. Moreover, inactivation of E2f1 rescued high glucose-induced ectopic division and cell death of retinal neurons, but not ectopic cell division of Müller glial cells and vascular phenotypes. This suggests that high glucose has direct but distinct effects on retinal neurons, glial cells and blood vessels, and that E2f1 mediates its effects on retinal neurons. These findings shed new light onto mechanisms of DR and the fetal retinal abnormalities associated with maternal diabetes, and suggest possible new therapeutic strategies.

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Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets

Cited by 6 publications

References 22 publications

Modeling inducible neuropathologies of the retina with differential phenotypes in organoids

Modeling inducible neuropathologies of the retina with differential phenotypes in organoids

Rb is required for retinal angiogenesis and lamination

E2f1 mediates high glucose-induced neuronal death in cultured mouse retinal explants

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