Heterozygous Meg2 Ablation Causes Intraocular Pressure Elevation and Progressive Glaucomatous Neurodegeneration

Reinhard, Jacqueline; Wiemann, Susanne; Joachim, Stephanie C; Palmhof, Marina; Woestmann, Julia; Denecke, Bernd; Wang, Yingchun; Downey, Gregory P.; Faissner, Andréas

doi:10.1007/s12035-018-1376-2

Cited by 12 publications

(17 citation statements)

References 102 publications

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“…In addition, an enhanced astrocyte reactivity in response to inflammatory signals is directly regulated by the ECM ( 83 ). Furthermore, RGC degeneration is accompanied by reactive astrogliosis, which results in a higher GFAP expression ( 51 , 58 , 84 – 86 ). In our study, we observed an upregulated Gfap expression and an increased GFAP immunostaining in retinal and optic nerve tissue of immunized WT mice, whereas absence of Tnc led to a missing reactive gliosis.…”

Section: Discussionmentioning

confidence: 99%

“…Both eyes were analyzed and 10 readings of each eye were averaged. IOP measurements were performed before immunization in WT and KO mice at 5 weeks of age with a rebound tonometer (TonoLab; Icare; Oy; Finland; n = 16/group) as previously described ( 50 , 51 ). After immunization, IOP was measured weekly in all four groups until the end of the study ( n = 8/group).…”

Section: Methodsmentioning

confidence: 99%

“…Scotopic full-field flash electroretinograms (ERG) recordings (HMsERG system, OcuScience, Henderson, NV, USA) were taken 10 weeks after immunization in all groups ( n = 5/group) as previously described ( 51 ). Mice were dark-adapted and anesthetized with a ketamine/xylazine mixture (120/16 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

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Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model

et al. 2020

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Previous studies demonstrated that retinal damage correlates with a massive remodeling of extracellular matrix (ECM) molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. Ten weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells, and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function were comparable in all groups. Although RGC loss was less severe in KO ONA, WT as well as KO mice displayed a significant cell loss after immunization. Compared to KO ONA, less βIII-tubulin + axons, and downregulated oligodendrocyte markers were noted in WT ONA optic nerves. In retina and optic nerve, we found an enhanced GFAP + staining area of astrocytes in immunized WT. A significantly higher number of retinal Iba1 + microglia was found in WT ONA, while a lower number of Iba1 + cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2 , and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb1 expression was measured in KO ONA animals. We conclude that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model for the first time offers the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model

et al. 2020

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“…Scotopic full-field flash electroretinogram (ERG) recordings (HMsERG system, OcuScience, Henderson, NV, United States) were performed 7 days after I/R ( n = 5/group) as described previously ( Schmid et al, 2014 ; Reinhard et al, 2019 ). In brief, mice were dark-adapted overnight before performing ERG recordings under dim red light.…”

Section: Methodsmentioning

confidence: 99%

“…For each primer set efficiencies were determined by a dilution series of 5, 25, and 125 ng cDNA. RT-qPCR analyses were performed with SYBR Green I in a Light Cycler 96 ® (Roche Applied Science, Mannheim, Germany) as described previously ( Reinhard et al, 2019 ). Expression was normalized against the constantly expressed housekeeping gene hypoxanthine guanine phosphoribosyl transferase ( Hprt ).…”

Section: Methodsmentioning

confidence: 99%

Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction

et al. 2021

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Retinal ischemia is a common pathomechanism in various eye diseases. Recently, evidence accumulated suggesting that the extracellular matrix (ECM) glycoprotein tenascin-C (Tnc) plays a key role in ischemic degeneration. However, the possible functional role of Tnc in retinal ischemia is not yet known. The aim of our study was to explore retinal function and rod-bipolar/photoreceptor cell degeneration in wild type (WT) and Tnc knock-out (KO) mice after ischemia/reperfusion (I/R) injury. Therefore, I/R was induced by increasing intraocular pressure in the right eye of wild type (WT I/R) and Tnc KO (KO I/R) mice. The left eye served as untreated control (WT CO and KO CO). Scotopic electroretinogram (ERG) recordings were performed to examine rod-bipolar and rod-photoreceptor cell function. Changes of Tnc, rod-bipolar cells, photoreceptors, retinal structure and apoptotic and synaptic alterations were analyzed by immunohistochemistry, Hematoxylin and Eosin staining, Western blot, and quantitative real time PCR. We found increased Tnc protein levels 3 days after ischemia, while Tnc immunoreactivity decreased after 7 days. Tnc mRNA expression was comparable in the ischemic retina. ERG measurements after 7 days showed lower a-/b-wave amplitudes in both ischemic groups. Nevertheless, the amplitudes in the KO I/R group were higher than in the WT I/R group. We observed retinal thinning in WT I/R mice after 3 and 7 days. Although compared to the KO CO group, retinal thinning was not observed in the KO I/R group until 7 days. The number of PKCα+ rod-bipolar cells, recoverin+ photoreceptor staining and Prkca and Rcvrn expression were comparable in all groups. However, reduced rhodopsin protein as well as Rho and Gnat1 mRNA expression levels of rod-photoreceptors were found in the WT I/R, but not in the KO I/R retina. Additionally, a lower number of activated caspase 3+ cells was observed in the KO I/R group. Finally, both ischemic groups displayed enhanced vesicular glutamate transporter 1 (vGlut1) levels. Collectively, KO mice showed diminished rod-photoreceptor degeneration and retinal dysfunction after I/R. Elevated vGlut1 levels after ischemia could be related to an impaired glutamatergic photoreceptor-bipolar cell signaling and excitotoxicity. Our study provides novel evidence that Tnc reinforces ischemic retinal degeneration, possibly by synaptic remodeling.

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Aus den Biowissenschaften

Süssmuth¹,

Bick²

2018

Nachr Chem

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Heterozygous Meg2 Ablation Causes Intraocular Pressure Elevation and Progressive Glaucomatous Neurodegeneration

Cited by 12 publications

References 102 publications

Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model

Loss of the Extracellular Matrix Molecule Tenascin-C Leads to Absence of Reactive Gliosis and Promotes Anti-inflammatory Cytokine Expression in an Autoimmune Glaucoma Mouse Model

Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction

Aus den Biowissenschaften

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