microRNA expression in the neural retina: Focus on Müller glia

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Müller glia are the predominant type of glia in the neural retina of vertebrates besides astrocytes and microglia. They establish strategic connections with all types of retinal neurons and their synapses, fulfilling special functions that are commonly accomplished by other glial cells in the brain. These functions include cellular debris removal, transmitter uptake and recycling, K+ pumping and water balance preservation, light guidance, the maintenance and regulation of the retinal blood barrier, and, occasionally, the initiation of the innate immunity responses (for review, see Newman, 2015; Reichenbach & Bringmann, 2013; Vecino, Rodriguez, Ruzafa, Pereiro, & Sharma, 2016). Because of these highly specialized functions, any imbalance in the physiology of Müller glia alters the normal function of the retina and consequently contributes to damage progress or the degeneration observed in common retinal diseases such as glaucoma, diabetic retinopathy (DR), or macular telangiectasia (reviewed in Bringmann et al., 2006; Bringmann & Wiedemann, 2012; Seitz, Ohlmann, & Tamm, 2013).
However, at least in some species such as teleost fish and amphibians, Müller glia also hold the answer to retinal regeneration. A striking feature of Müller glia is that in response to damage they are able to de‐differentiate, reenter the cell cycle, proliferate, behave as retinal progenitor cells (RPCs), and undergo neuronal differentiation (Das et al., 2006; Fischer & Reh, 2001; Gallina, Todd, & Fischer, 2013; Langhe et al., 2017). As a consequence, full functional recovery from de‐differentiated Müller cells may be attained in regenerative species (Otteson & Hitchcock, 2003; Raymond, Barthel, Bernardos, & Perkowski, 2006; Vihtelic, Soverly, Kassen, & Hyde, 2006). In nonregenerative species such as mammals, Müller glia respond to damage by becoming reactive and hypertrophic through a process that contributes to neurodegeneration rather than restoring visual function.
Nonetheless, paradigm‐shifting evidence has demonstrated that mammalian Müller glia may also de‐differentiate, acquire a progenitor phenotype and even differentiate to neuronal cell types (reviewed in Gallina et al., 2013; Goldman, 2014). Hence, mammalian Müller glia may express the molecular machinery required to induce the profound gene expression changes that would lead these processes.
Recent research has revealed substantive functions for microRNAs (miRNAs) in the retina (Lumayag et al., 2013; Fulzele et al., 2015; Krol et al., 2015; Sundermeier & Palczewski, 2012; 2016). These short noncoding RNAs have the ability to regulate target proteins by interfering with mRNA translation, affecting almost all cellular processes (Huntzinger & Izaurralde, 2011; Valencia‐Sanchez, Liu, Hannon, & Parker, 2006). miRNAs are subjected to differential or selective regulation among tissues, resulting in tissue‐specific or tissue‐enriched miRNA expression profiles (Karali et al., 2007, 2010; Lagos‐Quintana et al., 2002; Ryan, Oliveira‐Fernandes, & Lavker, 2006), and a number of retinal pathologies such as age‐related macular degeneration, glaucoma, and ischemia have been associated with altered miRNA expression (Bhattacharjee, Zhao, Dua, Rogaev, & Lukiw, 2016; He, Liu, Zhang, & Fan, 2016; Jayaram, Cepurna, Johnson, & Morrison, 2015; Palfi et al., 2016).
Most of the studies regarding miRNA and retinal physiology/pathology illustrate a global view of the tissue or focus on nonglial cells (Andreeva & Cooper, 2014; Sundermeier & Palczewski, 2012; Xu, Witmer, Lumayag, Kovacs, & Valle, 2007). However, miRNAs are great candidates not only for development of retinal pathology but also for the regulation of Müller glia responses, the maintenance of retinal homeostasis under physiological conditions, and perhaps even regenerative processes.
Novel strategies to exploit the regenerative capacities of mammalian Müller cells may be impelled by the identification of Müller glia–specific miRNA signatures and comparative studies of the mechanisms driving cell phenotypical alterations in regenerative and nonregenerative species.
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