Abstract
One of the primary obstacles in the application of retinal progenitor cells (RPCs) to the treatment of retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is their limited ability to proliferate and differentiate into specific retinal neurons. In this study, we revealed that repressor element-1-silencing transcription factor (REST), whose expression could be transcriptionally and post-transcriptionally mediated by retinoic acid (RA, one isomeride of a vitamin A derivative used as a differentiation-inducing agent in many disease treatments), plays a pivotal role in the regulation of proliferation and differentiation of RPCs. Our results show that direct knockdown of endogenous REST reduced RPC proliferation but accelerated RPC differentiation toward retinal neurons, which phenocopied the observed effects of RA on RPCs. Further studies disclosed that the expression level of REST could be downregulated by RA not only through upregulating microRNA (miR)-29a, which directly interacted with the 3′-untranslated region (3′-UTR) of the REST mRNA, but also through promoting REST proteasomal degradation. These results show us a novel functional protein, REST, which regulates RPC proliferation and differentiation, can be mediated by RA. Understanding the mechanisms of REST and RA in RPC fate determination enlightens a promising future for the application of REST and RA in the treatment of retinal degeneration diseases.
Highlights
Retinal progenitor cells (RPCs) are a side branch of neural progenitor cells that sustain the undifferentiated status with the potential for self-renewal and differentiation into retinal neuronal cells and have great potential to treat retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP)[1,2,3]
Following Cell Counting Kit-8 (CCK-8) analysis, there was significantly inhibited expansion in siREST-treated cultures for the following 48 h and 72 h, while there was no marked difference between the two groups on the first day (Fig. 1e), implying knockdown of the expression of repressor element-1silencing transcription factor (REST) reduce RPC proliferation
The quantitative polymerase chain reaction (qPCR) results showed that the expression levels of Ki-67 decreased notably in siREST-treated RPC cultures compared with the control group (Fig. 1f)
Summary
Retinal progenitor cells (RPCs) are a side branch of neural progenitor cells that sustain the undifferentiated status with the potential for self-renewal and differentiation into retinal neuronal cells and have great potential to treat retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP)[1,2,3]. Repressor element-1-silencing transcription factor (REST, known as neuron-restrictive silencer factor, NRSF) is a zinc-finger protein, which interacts with RE-1, exerting a gene silencing effect[10,11,12,13]. Wang et al Cell Death and Disease (2018)9:444 stem cells (ESCs) differentiation into neural progenitor cells (NPCs), REST is downregulated by proteasomal degradation. When transitioning from progenitor to mature neurons, REST and its corepressors dissociate from neuronal gene chromatin accompanied by its transcriptional repression[11,12]. The literature suggests that REST plays an important role in the generation of functional mature neurons. In aging and Alzheimer’s disease, REST exerts a neuronal protective effect through spurring stress response genes expression and suppressing genes that facilitate cell death and disease pathology[15]. As RPCs are one of the promising cell resources in the treatment of retinal degeneration diseases, it is worth detecting the role of REST in RPC fate determination
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