Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast, Yap+/- adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context, Yap haploinsufficiency in aged individuals results in Müller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Müller cell specific conditional Yap knockout mice. Together, this study highlights a novel YAP function in Müller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human.

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Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy

Cell Death and Disease ◽

10.1038/s41419-020-02860-9 ◽

2020 ◽

Vol 11 (8) ◽

Cited By ~ 1

Author(s):

Christel Masson ◽

Diana García-García ◽

Juliette Bitard ◽

Élodie-Kim Grellier ◽

Jérôme E. Roger ◽

...

Keyword(s):

Late Onset ◽

Müller Cell ◽

Cone Dystrophy ◽

Cell Dysfunction ◽

Muller Cell

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Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Journal of Experimental Medicine ◽

10.1084/jem.20131494 ◽

2014 ◽

Vol 211 (2) ◽

pp. 281-295 ◽

Cited By ~ 47

Author(s):

Jiong Hu ◽

Rüdiger Popp ◽

Timo Frömel ◽

Manuel Ehling ◽

Khader Awwad ◽

...

Keyword(s):

Notch Signaling ◽

Notch Signaling Pathway ◽

Müller Cell ◽

Muller Glia ◽

Müller Glia ◽

Lipid Profiling ◽

Glia Cells ◽

Retinal Angiogenesis ◽

Muller Cell

Cytochrome P450 (CYP) epoxygenases generate bioactive lipid epoxides which can be further metabolized to supposedly less active diols by the soluble epoxide hydrolase (sEH). As the role of epoxides and diols in angiogenesis is unclear, we compared retinal vasculature development in wild-type and sEH−/− mice. Deletion of the sEH significantly delayed angiogenesis, tip cell, and filopodia formation, a phenomenon associated with activation of the Notch signaling pathway. In the retina, sEH was localized in Müller glia cells, and Müller cell–specific sEH deletion reproduced the sEH−/− retinal phenotype. Lipid profiling revealed that sEH deletion decreased retinal and Müller cell levels of 19,20–dihydroxydocosapentaenoic acid (DHDP), a diol of docosahexenoic acid (DHA). 19,20-DHDP suppressed endothelial Notch signaling in vitro via inhibition of the γ-secretase and the redistribution of presenilin 1 from lipid rafts. Moreover, 19,20-DHDP, but not the parent epoxide, was able to rescue the defective angiogenesis in sEH−/− mice as well as in animals lacking the Fbxw7 ubiquitin ligase, which demonstrate strong basal activity of the Notch signaling cascade. These studies demonstrate that retinal angiogenesis is regulated by a novel form of neuroretina–vascular interaction involving the sEH-dependent generation of a diol of DHA in Müller cells.

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Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents

Cellular Physiology and Biochemistry ◽

10.1159/000460514 ◽

2017 ◽

Vol 41 (3) ◽

pp. 960-972 ◽

Cited By ~ 21

Author(s):

Ao-Wang Qiu ◽

Qing-Huai Liu ◽

Jun-Ling Wang

Keyword(s):

Diabetic Retinopathy ◽

Intravitreal Injection ◽

Cell Function ◽

Autoimmune Diabetes ◽

Müller Cell ◽

Cell Dysfunction ◽

Junction Protein ◽

Neutralizing Monoclonal Antibody ◽

Muller Cell

Background/Aims: Interleukin (IL)-17A, a proinflammatory cytokine, has been implicated in several autoimmune diseases. However, it is unclear whether IL-17A is involved in diabetic retinopathy (DR), one of the most serious complications of autoimmune diabetes. This study aimed to demonstrate that IL-17A exacerbates DR by affecting retinal Müller cell function. Methods: High glucose (HG)-treated rat Müller cell line (rMC-1) was exposed to IL-17A, anti-IL-17A-neutralizing monoclonal antibody (mAb) or/and anti-IL-17 receptor (R)A-neutralizing mAb for 24 h. For in vivo study, DR was induced by intraperitoneal injections of streptozotocin (STZ). DR model mice were treated with anti-IL-17A mAb or anti-IL-17RA mAb in the vitreous cavity. Mice that were prepared for retinal angiography were sacrificed two weeks after intravitreal injection, while the rest were sacrificed two days after intravitreal injection. Results: IL-17A production and IL-17RA expression were increased in both HG-treated rMC-1 and DR retina. HG induced rMC-1 activation and dysfunction, as determined by the increased GFAP, VEGF and glutamate levels as well as the downregulated GS and EAAT1 expression. IL-17A exacerbated the HG-induced rMC-1 functional disorders, whereas either anti-IL-17A mAb or anti-IL-17RA mAb alleviated the HG-induced rMC-1 disorders. Intravitreal injections with anti-IL-17A mAb or anti-IL-17RA mAb in DR model mice reduced Müller cell dysfunction, vascular leukostasis, vascular leakage, tight junction protein downregulation and ganglion cell apoptosis in the retina. Conclusions: IL-17A aggravates DR-like pathology at least partly by impairing retinal Müller cell function. Blocking IL-17A is a potential therapeutic strategy for DR.

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Possibility of Müller Cell Dysfunction as the Pathogenesis of Paclitaxel Maculopathy

Ophthalmic Surgery Lasers and Imaging Retina ◽

10.3928/23258160-20151214-14 ◽

2016 ◽

Vol 47 (1) ◽

pp. 81-84 ◽

Cited By ~ 12

Author(s):

Shintaro Nakao ◽

Yasuhiro Ikeda ◽

Yasunori Emi ◽

Tatsuro Ishibashi

Keyword(s):

Müller Cell ◽

Cell Dysfunction ◽

Muller Cell

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Demonstration of Retinal Glycogen with Silver Methenamine

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066875 ◽

1971 ◽

Vol 29 ◽

pp. 564-565

Author(s):

A. W. Sedar ◽

G. H. Bresnick

Keyword(s):

Lactic Acid ◽

Chromic Acid ◽

Periodic Acid ◽

Müller Cell ◽

External Limiting Membrane ◽

Electron Microscope Level ◽

Reactive Process ◽

Inner Limiting Membrane ◽

Muller Cell ◽

And Migration

After experimetnal damage to the retina with a variety of procedures Müller cell hypertrophy and migration occurs. According to Kuwabara and others the reactive process in these injuries is evidenced by a marked increase in amount of glycogen in the Müller cells. These cells were considered originally supporting elements with fiber processes extending throughout the retina from inner limiting membrane to external limiting membrane, but are known now to have high lactic acid dehydrogenase activity and the ability to synthesize glycogen. Since the periodic acid-chromic acid-silver methenamine technique was shown to demonstrate glycogen at the electron microscope level, it was selected to react with glycogen in the fine processes of the Müller cell that ramify among the neural elements in various layers of the retina and demarcate these cells cytologically. The Rhesus monkey was chosen as an example of a well vascularized retina and the rabbit as an example of a avascular retina to explore the possibilities of the technique.

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Faculty Opinions recommendation of Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718245184.793490808 ◽

2014 ◽

Author(s):

William A Muller

Keyword(s):

Notch Signaling ◽

Muller Glia ◽

Müller Glia ◽

Glia Cells ◽

Retinal Angiogenesis

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Faculty Opinions recommendation of Stimulation of functional neuronal regeneration from Müller glia in adult mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727841108.793535182 ◽

2017 ◽

Author(s):

Jun Takahashi

Keyword(s):

Muller Glia ◽

Neuronal Regeneration ◽

Müller Glia ◽

Adult Mice ◽

Stimulation Of

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VEGF Mediates Retinal Müller Cell Viability and Neuroprotection through BDNF in Diabetes

Biomolecules ◽

10.3390/biom11050712 ◽

2021 ◽

Vol 11 (5) ◽

pp. 712

Author(s):

Yun-Zheng Le ◽

Bei Xu ◽

Ana J. Chucair-Elliott ◽

Huiru Zhang ◽

Meili Zhu

Keyword(s):

Specific Protein ◽

Müller Cell ◽

Dependent Manner ◽

Vascular Abnormalities ◽

Extracellular Signal ◽

Muller Cell ◽

Protein Kinase Akt ◽

Sirna Knockdown ◽

Endothelial Growth Factor ◽

Dose Dependent

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood–retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities.

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