Translatomic response of retinal Müller glia to acute and chronic stress

Chucair-Elliott, Ana J.; Ocañas, Sarah R.; Pham, Kevin D.; Veldt, Michael Van Der; Cheyney, Ashley; Stanford, David R.; Gurley, Jami; Elliott, Michael H.; Freeman, Willard M.

doi:10.1016/j.nbd.2022.105931

Cited by 17 publications

(5 citation statements)

References 61 publications

(142 reference statements)

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“…Consistent with our results, a recent study (Chucair‐Elliott et al, 2022) showed that Müller glia activate the CHOP/ATF4 pathway under stress conditions. Chucair‐Elliott et al found that retina stress from optic nerve crush leads to a Müller glia translatomic response that includes upregulated expression of Ddit3 (CHOP) and Atf4 .…”

Section: Discussionsupporting

confidence: 93%

“…Chucair‐Elliott et al found that retina stress from optic nerve crush leads to a Müller glia translatomic response that includes upregulated expression of Ddit3 (CHOP) and Atf4 . The DEGs (including Ddit3 [CHOP] and Atf4 ) were found to be enriched in biological processes following a myriad of stress conditions: regulation of DNA‐templated transcription in response to stress, response to starvation, response to wounding, positive regulation of cytokine production, neuron death, and response to molecule of bacterial origin (Chucair‐Elliott et al, 2022). We also noted that Atf4 gene was significantly more abundant in Müller glia than astrocytes in P30 mouse retinas (Figure S12).…”

Section: Discussionmentioning

confidence: 99%

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ER‐stress response in retinal Müller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina

Palko,

Benoit,

Yao

et al. 2024

Glia

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Alzheimer's Disease (AD) pathogenesis is thought to begin up to 20 years before cognitive symptoms appear, suggesting the need for more sensitive diagnostic biomarkers of AD. In this report, we demonstrated pathological changes in retinal Müller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock‐in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30). Despite RTN3 being a canonically neuronal protein, this increase was noted in the retinal Müller glia, confirmed by immunohistochemical characterization. Further unbiased transcriptomic assays of the P30 NLGF retina revealed that retinal Müller glia were the most sensitive responding cells in this mouse retina, compared with other cell types including photoreceptor cells and ganglion neurons. Pathway analyses of differentially expressed genes in glia cells showed activation of ER stress response via the upregulation of unfolded protein response (UPR) proteins such as ATF4 and CHOP. Early elevation of RTN3 in response to challenges by toxic Aβ likely facilitated UPR. Altogether, these findings suggest that Müller glia act as a sentinel for AD pathology in the retina and should aid for both intervention and diagnosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

ER‐stress response in retinal Müller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina

Palko,

Benoit,

Yao

et al. 2024

Glia

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“… 32 We have used this experimental design of TRAP and INTACT and a floxed NuTRAP mouse model to better understand the transcriptional and epigenetic changes with age in various cell types. 38 , 39 , 40 The key findings from this study are that age of Tam induction had no significant effect on the efficiency or specificity of Cre recombinase induction, isolation of microglial specific translatome profiles, or the ability to identify age-related microglial translatomic alterations. These results demonstrate that experimental designs utilizing early life and late-life Tam administration are valid approaches for microglial studies and most likely generalizable to other inducible Cre mouse models.…”

Section: Introductionmentioning

confidence: 73%

Specificity and efficiency of tamoxifen-mediated Cre induction is equivalent regardless of age

Kellogg,

Pham,

et al. 2023

iScience

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“…Considering the early and pronounced increase in pSTAT3 signaling, we next employed immunohistochemistry on retinal cross-sections 12 hours after OSM treatment to localize pSTAT3. Using transgenic mice that express green fluorescent protein (GFP) linked to ALDH1L1, a Müller glia cell marker, 43 we identified prominent pSTAT3 signal in the inner nuclear layer (INL), where nuclei of Müller cells are located, as well as in the ganglion cell layer (GCL), were ganglion cell nuclei, and isolectin positive vascular structures ( Fig. 3 B).…”

Section: Resultsmentioning

confidence: 99%

Oncostatin M Reduces Pathological Neovascularization in the Retina Through Müller Cell Activation

Rapp,

Hospach,

Liang

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose Continuous vision loss due to vasoproliferative eye disease still represents an unsolved issue despite anti-vascular endothelial growth factor (VEGF) therapy. The impact of signal transducer and activator of transcription 3 (STAT3) signaling on retinal angiogenesis and its potential use as a therapeutic target remain controversial. In vitro, oncostatin M (OSM), as a strong STAT3 activator, possesses robust proangiogenic activity. This study investigated to what extent the proangiogenic effects of OSM translate to the in vivo setting of vasoproliferative eye disease. Methods The in vitro effect of OSM on endothelial cells was investigated in the spheroid sprouting assay and through RNA sequencing. The mouse model for oxygen-induced retinopathy (OIR) was used to evaluate the impact of OSM in vivo. Signaling patterns were measured by western blot and retinal cryosections. Primary Müller cell cultures were used to evaluate the effect of OSM on the Müller cell secretome. Murine retinal vascular endothelial cells were isolated from OIR retinas using fluorescence-activated cell sorting (FACS) and were used for RNA sequencing. Results Although OSM induced pro-angiogenic responses in vitro, in the OIR model intravitreal injection of OSM reduced retinal neovascularization by 65.2% and vaso-obliteration by 45.5% in Müller cells. Injecting OSM into the vitreous activated the STAT3 signaling pathway in multiple retinal cell types, including Müller cells. In vitro, OSM treatment increased CXCL10 secretion. RNA sequencing of sorted vascular endothelial cells at OIR P17 following OSM treatment indicated downregulation of angiogenesis- and mitosis-associated genes. Conclusions In vivo, OSM reveals a beneficial angiomodulatory effect by activating Müller cells and changing their secretome. The data highlight contradictions between cytokine-induced effects in vitro and in vivo depending on the cell types mediating the effect.

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Translatomic response of retinal Müller glia to acute and chronic stress

Cited by 17 publications

References 61 publications

ER‐stress response in retinal Müller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina

ER‐stress response in retinal Müller glia occurs significantly earlier than amyloid pathology in the Alzheimer's mouse brain and retina

Specificity and efficiency of tamoxifen-mediated Cre induction is equivalent regardless of age

Oncostatin M Reduces Pathological Neovascularization in the Retina Through Müller Cell Activation

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