Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury

Mak, Heather; Ng, Shuk Han; Ren, Tianmin; Ye, Cong; Leung, Christopher Kai-Shun

doi:10.1016/j.exer.2020.107938

Cited by 23 publications

(19 citation statements)

References 23 publications

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“…RGCs (27). Researches con rmed that a genetic deletion of PTEN, SOCS3, or PTEN/SOCS3 allows partial axon regeneration in the optic nerve after optic nerve crush (28,29). In our study, it was found that Y27632 can also promote the axon growth of Müller cell differentiated (35).…”

Section: Discussionsupporting

confidence: 57%

“…A high-throughput gene pro ling study revealed that the deletion of Klf9 gene substantially promotes optic nerve regeneration in adults RGCs (27). Researches con rmed that a genetic deletion of PTEN, SOCS3, or PTEN/SOCS3 allows partial axon regeneration in the optic nerve after optic nerve crush (28,29). Inhibition of Mdm4 in the eye and spinal cord promotes axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury (30).…”

Section: Discussionmentioning

confidence: 99%

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STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

Zhou¹,

Wang²,

Peng³

et al. 2020

Preprint

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BackgroundMüller differentiated RGCs have potential therapeutic value for glaucoma. However, axonal regeneration of differentiated RGCs has been a difficult problem. Studies have confirmed that STAT3 and Y27632 play essential roles in regulating neuronal axon regeneration. Whether STAT3 and Y27632 can induce the Müller differentiated RGCs axon regeneration is still unknown.MethodRetina Müller cells were isolated and purified from Day 21 SD rats’ retina and were differentiated into retinal stem cells. The stem cells were randomly divided into five groups (control group, AAV-STAT3 group, shSTAT3 group, Y27632 group and AAV-STAT3 + Y27632 group). The axon length in each group were measured by ImageJ. Immunofluorescence were used to label the RGCs. The mRNA level of pluripotent associated and differentiation-associated proteins was analysed by qRT-PCR. Stem cells in different groups were injected into mice model of glaucoma. Immunohistochemical, Immunohistochemistry and OCT were performed to access RGC layer thickness in glaucoma model. VEP was used to detect the optic nerve conduction function.ResultsIn this study, we found that overexpression of STAT3 could promote the growth of RGCs axons generated by Müller cell differentiation. Combined with Y27632, axonal regeneration was significantly longer than that of the STAT3 group. However, after STAT3 was knocked out, axonal regeneration significantly decreased or even stopped. The mRNA levels of Esrrb, Prdm14, Sox2, and Rex1 in Müller differentiated RGCs after overexpression STAT3 combined with Y27632 were significantly increased, while the mRNA levels of Nestin, Eomes, Mixl1 and Gata4 were significantly decreased. The mRNA levels of Socs3, Pten, Klf9, and Mdm4 were significantly decreased, while the mRNA levels of Dclk2, Armcx1, C-MYC, and Nrn1 were significantly increased. The mRNA levels of differentiation and pluripotency marker genes showed opposite results after STAT3 deletion. After injecting Müller differentiated RGCs intervened by STAT3 combined with Y27632 into the eyes of the glaucoma model mice, the axon length, OCT displayed RGC layer thickness and the electrophysiology indicated by VEP were superior to those of the glaucoma model group.ConclusionsThese findings suggested that STAT3 combined with Y27632 can significantly improve the axonal growth level of RGCs, and reveal the potential mechanism to induce pluripotency of RGCs.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

Zhou¹,

Wang²,

Peng³

et al. 2020

Preprint

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“…We saw a dose-dependent reduction in both ptena and ptenb genes (Figure 7J), as well as protein expression (Figure 7K) in SB431542-treated retina at 2dpi. Promoter analysis of ptena and ptenb genes revealed the presence of typical 5GC sites, GGC(GC)/CG, on which pSmad3 binds to activate gene expression (Martin-Malpartida et al, 2017). We further confirmed the occupancy of these 5GC elements by pSmad3 by ChIP assay using pSmad3-specific antibodies at 2dpi (Figure 7L).…”

Section: Regulation Of Pten Expression During Retina Regenerationsupporting

confidence: 58%

“…Pharmacological inhibition of PTEN has been proposed as a strategy to enhance tissue regeneration (Borges et al, 2020). Despite the knowledge on the relevance of PTEN during axon regeneration (Kurimoto et al, 2010;Mak et al, 2020;Ohtake et al, 2015), its importance during retina regeneration remained underexplored. In this study of retina regeneration, we explored the significance of Pten regulation and its downstream molecular events, which are well-elucidated in various tumorigenic pathways.…”

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confidence: 99%

Temporal regulation of Pten is essential for retina regeneration in zebrafish

Gupta

Sharma

Choudhary

et al. 2021

Preprint

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Unlike mammals, zebrafish possess a remarkable ability to regenerate damaged retina after an acute injury. Retina regeneration in zebrafish involves the induction of Müller glia-derived progenitor cells (MGPCs) exhibiting stem cell-like characteristics, which are capable of restoring all retinal cell-types. Here, we explored the importance of Phosphatase and tensin homolog (Pten), a dual-specificity phosphatase and tumor suppressor during retina regeneration. The Pten undergo rapid downregulation in the Müller glia and is absent in MGPCs, which is essential to trigger Akt-mediated cell proliferation to cause retina regeneration. We found that the forced downregulation of Pten accelerates MGPCs formation, while its overexpression restricts the regenerative response. We observed that Pten regulates the proliferation of MGPCs not only through Akt pathway but also by Mmp9/Notch signaling. Mmp9-activity is essential to induce the proliferation of MGPCs in the absence of Pten. Lastly, we show that Pten expression is fine-tuned through Mycb/histone deacetylase1 and Tgf-β signaling. The present study emphasizes on the stringent regulation of Pten and its crucial involvement during the zebrafish retina regeneration.

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“…Dendritic retraction is believed to be one of the earliest responses of the RGCs to stress, and can be detected prior to axonal loss [ 17 , 26 , 27 , 28 ]. Multiple studies show dendritic changes of αRGCs and other RGC types in acute experimental [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] as well in genetic [ 36 ] murine glaucoma models. Likewise, our observations in the chronic microbead model disclosed an aberrant dendritic retraction of αRGCs and a lower area under the Sholl curve at five weeks after microbead injection.…”

Section: Discussionmentioning

confidence: 99%

A Fair Assessment of Evaluation Tools for the Murine Microbead Occlusion Model of Glaucoma

Claes

Santos

Masin

et al. 2021

IJMS

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Despite being one of the most studied eye diseases, clinical translation of glaucoma research is hampered, at least in part, by the lack of validated preclinical models and readouts. The most popular experimental glaucoma model is the murine microbead occlusion model, yet the observed mild phenotype, mixed success rate, and weak reproducibility urge for an expansion of available readout tools. For this purpose, we evaluated various measures that reflect early onset glaucomatous changes in the murine microbead occlusion model. Anterior chamber depth measurements and scotopic threshold response recordings were identified as an outstanding set of tools to assess the model’s success rate and to chart glaucomatous damage (or neuroprotection in future studies), respectively. Both are easy-to-measure, in vivo tools with a fast acquisition time and high translatability to the clinic and can be used, whenever judged beneficial, in combination with the more conventional measures in present-day glaucoma research (i.e., intraocular pressure measurements and post-mortem histological analyses). Furthermore, we highlighted the use of dendritic arbor analysis as an alternative histological readout for retinal ganglion cell density counts.

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Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury

Cited by 23 publications

References 23 publications

STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

Temporal regulation of Pten is essential for retina regeneration in zebrafish

A Fair Assessment of Evaluation Tools for the Murine Microbead Occlusion Model of Glaucoma

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Impact of PTEN/SOCS3 deletion on amelioration of dendritic shrinkage of retinal ganglion cells after optic nerve injury

Cited by 23 publications

References 23 publications

­­STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

­­STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

Temporal regulation of Pten is essential for retina regeneration in zebrafish

A Fair Assessment of Evaluation Tools for the Murine Microbead Occlusion Model of Glaucoma

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STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells

STAT3 combines with Rho-ROCK signaling pathway inhibitor, regulate axon growth of ganglion cells derived from retinal Müller cells