Comparison of proteomic profiles in the zebrafish retina during experimental degeneration and regeneration

Eastlake, Karen; Heywood, Wendy; Tracey‐White, Dhani; Aquino, Érika Carvalho de; Bliss, Emily; Vasta, Gerardo R.; Mills, Kevin; Khaw, PT; Moosajee, Mariya; Limb, G. Astrid

doi:10.1038/srep44601

Cited by 22 publications

(19 citation statements)

References 45 publications

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“…Moreover, astrocyte-derived Gal1 has been proposed to play a role in neuromodulation and microglia polarization in a model of multiple sclerosis [24] and in axonal degeneration in a model of amyotrophic lateral sclerosis [62]. Recently, it has been observed that Gal1 is upregulated 2-fold in zebrafish retina during experimental degeneration [63], suggesting that it could play an important role in the repair of the zebrafish retina by providing a permissible environment for regeneration. However, since neural retina displays substantial differences with other nervous system circuits, further studies are needed to dissect the role of Gal1 in retinal neurodegeneration in different organisms.…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF

et al. 2017

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Neovascular retinopathies are leading causes of irreversible blindness. Although vascular endothelial growth factor (VEGF) inhibitors have been established as the mainstay of current treatment, clinical management of these diseases is still limited. As retinal impairment involves abnormal neovascularization and neuronal degeneration, we evaluated here the involvement of galectin-1 in vascular and non-vascular alterations associated with retinopathies, using the oxygen-induced retinopathy (OIR) model. Postnatal day 17 OIR mouse retinas showed the highest neovascular profile and exhibited neuro-glial injury as well as retinal functional loss, which persisted until P26 OIR. Concomitant to VEGF up-regulation, galectin-1 was highly expressed in P17 OIR retinas and it was mainly localized in neovascular tufts. In addition, OIR induced remodelling of cell surface glycophenotype leading to exposure of galectin-1-specific glycan epitopes. Whereas VEGF returned to baseline levels at P26, increased galectin-1 expression persisted until this time period. Remarkably, although anti-VEGF treatment in P17 OIR improved retinal vascularization, neither galectin-1 expression nor non-vascular and functional alterations were attenuated. However, this functional defect was partially prevented in galectin-1-deficient (Lgals1−/−) OIR mice, suggesting the importance of targeting both VEGF and galectin-1 as non-redundant independent pathways. Supporting the clinical relevance of these findings, we found increased levels of galectin-1 in aqueous humor from patients with proliferative diabetic retinopathy and neovascular glaucoma. Thus, using an OIR model and human samples, we identified a role for galectin-1 accompanying vascular and non-vascular retinal alterations in neovascular retinopathies.

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Section: Discussionmentioning

confidence: 99%

Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF

et al. 2017

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“…Histone H2B is one subunit of the histone H2A-H2B heterodimer [81], a key histone component [82]. Histone H2B is up-regulated in zebrafish retina undergoing regeneration [83]. These proteins are highlighted as markers of the retina, which clearly demonstrate the retinal expansion observed by H&E staining.…”

Section: Discussionmentioning

confidence: 99%

Gclc deletion in surface-ectoderm tissues induces microphthalmia

Thompson

Chen

Philippe

et al. 2019

Preprint

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Glutamate cysteine ligase catalytic subunit (Gclc) is the catalytic subunit for the glutamate-cysteine ligase (Gcl) enzyme. Gcl catalyzes the rate limiting step in glutathione (GSH) synthesis. Gclc is highly expressed in the developing eye. To define the regulatory role of Gclc in eye development, we developed a novel, Le-Cre transgene-driven, Gclc knockout mouse model. Gclc f/f /Le-Cre Tg/mice present with deformation of the retina, cornea, iris, and lens, consistent with a microphthalmia phenotype. Controlling for the microphthalmia phenotype of Gclc wt/wt /Le-Cre Tg/mice revealed that Gclc f/f /Le-Cre Tg/mice have a more severe microphthalmia phenotype. Thus, the loss of Gclc expression exacerbates the microphthalmia phenotype in Le-Cre mice.Gclc f/f /Le-Cre Tg/eyes present with reduced retinal and lens epithelium proliferation and increased lens cell death. Imaging mass spectrometry of ocular tissues revealed changes in the intensity and distribution of several lipid species and proteins in the retina and corneas of Gclc f/f /Le-Cre Tg/eyes. Lastly, using splice-blocking morpholinos and CRISPR/Cas9, we created two gclc knockdown zebrafish models, both of which display a microphthalmia phenotype. Combined, the mouse and zebrafish results indicate that, in chordates, Gclc has a conserved role in regulating eye development. In summary, these novel animal models are useful tools for elucidating the mechanisms involved in microphthalmia development.≈ 11% of the cases [1]. Currently, there is no cure for the severe loss of vision associated with microphthalmia. While surgical treatments exist, they only address the cosmetic abnormalities associated with microphthalmia [15]. However, recent research demonstrating the efficacy of nonsense suppression (inhibiting the effect of a nonsense mutation by pharmacologically increasing the likelihood of a near cognate aminoacyl-tRNA substitution) to rescue lens development when administered postnatally in a Pax6-deficient mouse model has provided hope that treatments for microphthalmia can be developed [16]. Clearly, a more complete understanding of the mechanisms regulating lens development should accelerate the discovery of preventative strategies and/or novel therapeutic treatments for microphthalmia. Glutathione (GSH), an intracellular antioxidant, is highly abundant in the eye, with concentrations of 20mM or more occurring in the lens cortex and epithelium [17, 18]. It is important for physiological detoxification of electrophiles and oxidants in the lens cortex and epithelium [19]. Through these functions, GSH maintains lens clarity and, as such, a decline in GSH levels is associated with cataract development [20, 21]. GSH biosynthesis involves a two-step enzymatic process [22] involving glutamate-cysteine ligase (GCL) followed by glutathione synthase (GSS). GCL, the rate limiting step in GSH synthesis, comprises a catalytic subunit (GCLC) and a modifier subunit (GCLM). Impaired GCLC or GCLM function limits GSH synthesis and reduces intracellular GSH concentrations. Th...

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“…The cytoskeleton and membrane transport proteins were altered during regeneration, with the highest fold-change upregulation observed for β-2 tubulin A, histone H2B and brain type fatty acid binding protein. In addition, via gene ontology analysis, reduced metabolic processing and increased fibrin clot formation during degeneration were observed when compared to that in the normal retina (Eastlake et al, 2017). However, further investigations of the energy metabolism of immune cells during zebrafish regeneration are needed.…”

Section: Metabolism and Regenerationmentioning

confidence: 99%

Understanding the Metabolic Profile of Macrophages During the Regenerative Process in Zebrafish

2019

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In contrast to mammals, lower vertebrates, including zebrafish (Danio rerio), have the ability to regenerate damaged or lost tissues, such as the caudal fin, which makes them an ideal model for tissue and organ regeneration studies. Since several diseases involve the process of transition between fibrosis and tissue regeneration, it is necessary to attain a better understanding of these processes. It is known that the cells of the immune system, especially macrophages, play essential roles in regeneration by participating in the removal of cellular debris, release of pro-and anti-inflammatory factors, remodeling of components of the extracellular matrix and alteration of oxidative patterns during proliferation and angiogenesis. Immune cells undergo phenotypical and functional alterations throughout the healing process due to growth factors and cytokines that are produced in the tissue microenvironment. However, some aspects of the molecular mechanisms through which macrophages orchestrate the formation and regeneration of the blastema remain unclear. In the present review, we outline how macrophages orchestrate the regenerative process in zebrafish and give special attention to the redox balance in the context of tail regeneration.

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Comparison of proteomic profiles in the zebrafish retina during experimental degeneration and regeneration

Cited by 22 publications

References 45 publications

Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF

Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF

Gclc deletion in surface-ectoderm tissues induces microphthalmia

Understanding the Metabolic Profile of Macrophages During the Regenerative Process in Zebrafish

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