scholarly journals Müller Glia Are a Major Cellular Source of Survival Signals for Retinal Neurons in Diabetes

Diabetes ◽  
2015 ◽  
Vol 64 (10) ◽  
pp. 3554-3563 ◽  
Author(s):  
Shuhua Fu ◽  
Shuqian Dong ◽  
Meili Zhu ◽  
David M. Sherry ◽  
Changyun Wang ◽  
...  
Keyword(s):  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons ◽  
Cellular Source ◽  
Survival Signals

scholarly journals Ldb1 and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in retina

2017 ◽  
Author(s):  
Jimmy de Melo ◽  
Anand Venkataraman ◽  
Brian S. Clark ◽  
Cristina Zibetti ◽  
Seth Blackshaw
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Amacrine Cells ◽  
Negative Regulator ◽  
Wide Field ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons ◽  
Bhlh Factors

AbstractPrecise control of the relative ratio of retinal neurons and glia generated during development is essential for visual function. We show that Lhx2, which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a critical role in the development of retinal neurons. Overexpression of Lhx2, and its transcriptional coactivator Ldb1, triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis. Lhx2/Ldb1 overexpression also induced the formation of wide-field amacrine cells (wfACs). In contrast Rnf12, which encodes a negative regulator of LDB1, is necessary for the initiation of retinal gliogenesis. We also show that LHX2 protein binds upstream of multiple neurogenic bHLH factors including Ascl1 and Neurog2, which are necessary for suppression of gliogenesis and wfAC formation respectively, and activates their expression. Finally, we demonstrate that the relative level of the LHX2-LDB1 complex in the retina decreases in tandem with the onset of gliogenesis. These findings show that control of Lhx2 function by Ldb1 and Rnf12 acts as a molecular mechanism underpinning the coordinated differentiation of neurons and Müller glia in postnatal retina.Significance StatementThe molecular mechanisms that control the ratio neurons and glia that are generated by neuronal progenitors remain unclear. Here we show that Lhx2, a transcription factor essential for retinal gliogenesis, also controls development of retinal neurons. The Lhx2 coactivator Ldb1 promotes Lhx2-dependent neurogenesis, while the Lhx2 corepressor Rnf12 is necessary and sufficient for retinal gliogenesis. Furthermore, Lhx2 directly regulates expression of bHLH factors that promote neural development, which are necessary for Lhx2-dependent neurogenesis. Finally, we show that levels of the LHX2-LDB1 complex, which activates transcription, drop as gliogenesis begins. Dynamic regulation of Lhx2 activity by Ldb1 and Rnf12 thus controls the relative levels of retinal neurogenesis and gliogenesis, and may have similar functions elsewhere in the developing nervous system.

scholarly journals Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

2015 ◽  
Vol 273 ◽  
pp. 114-125 ◽  
Author(s):  
Donika Gallina ◽  
Christopher Paul Zelinka ◽  
Colleen M. Cebulla ◽  
Andy J. Fischer
Keyword(s):  
Glucocorticoid Receptors ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons

scholarly journals Nuclear Factor I in neurons, glia and during the formation of Muller glia-derived progenitor cells in avian, porcine and primate retinas

2021 ◽  
Author(s):  
Heithem El-Hodiri ◽  
Warren Campbell ◽  
Lisa Kelly ◽  
Evan Hawthorn ◽  
Maura Schwartz ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Mouse Retina ◽  
Nuclear Factor ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons ◽  
Intrinsic Factors ◽  
Factor I ◽  
Chick Retina ◽  
Nuclear Factor I

The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly being revealed. Isoforms of Nuclear Factor I (NFI) are cell-intrinsic factors that limit neurogenic potential; these factors are required for the formation of MG in the developing mouse retina (Clark et al., 2019) and deletion of these factors reprograms MG into neuron-like cells in mature mouse retina (Hoang et al., 2020). Accordingly, we sought to characterize the patterns of expression NFIs in the developing, mature and damaged chick retina. In addition, we characterized patterns of expression of NFIs in the retinas of large mammals, pigs and monkeys. Using a combination of single cell RNA-sequencing (scRNA-seq) and immunolabeling we probed for patterns of expression. In embryonic chick, levels of NFIs are very low in early E5 (embryonic day 5) retinal progenitor cells (RPCs), up-regulated in E8 RPCs, further up-regulated in differentiating MG at E12 and E15. NFIs are maintained in mature resting MG, microglia and neurons. Levels of NFIs are reduced in activated MG in retinas treated with NMDA and/or insulin+FGF2, and further down-regulated in proliferating MGPCs. However, levels of NFIs in MGPCs were significantly higher than those seen in RPCs. Immunolabeling for NFIA and NFIB closely matched patterns of expression revealed in different types of retinal neurons and glia, consistent with findings from scRNA-seq. In addition, we find expression of NFIA and NFIB through progenitors in the circumferential marginal zone at the far periphery of the retina. We find similar patterns of expression for NFIs in scRNA-seq databases for pig and monkey retinas. Patterns of expression of NFIA and NFIB were validated with immunofluorescence in pig and monkey retinas wherein these factors were predominantly detected in MG and a few types of inner retinal neurons. In summary, NFIA and NFIB are prominently expressed in developing chick retina and by mature neurons and glia in the retinas of chicks, pigs and monkeys. Although levels of NFIs are decreased in chick, in MGPCs these levels remain higher than those seen in neurogenic RPCs. We propose that the neurogenic potential of MGPCs in the chick retina is suppressed by NFIs.

scholarly journals Reprogramming Müller Glia to Regenerate Retinal Neurons

2020 ◽  
Vol 6 (1) ◽  
pp. 171-193 ◽  
Author(s):  
Manuela Lahne ◽  
Mikiko Nagashima ◽  
David R. Hyde ◽  
Peter F. Hitchcock
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Current Knowledge ◽  
Cellular Reprogramming ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons ◽  
Age Related

In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.

scholarly journals Cannabinoid signaling promotes the reprogramming of Muller glia into proliferating progenitor cells.

2021 ◽  
Author(s):  
Warren Campbell ◽  
Sydney Blum ◽  
Alana Reske ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Expression Patterns ◽  
Synaptic Function ◽  
Muller Glia ◽  
Müller Glia ◽  
Rna Seq ◽  
Retinal Neurons ◽  
Pharmacological Agents ◽  
Retinal Microglia ◽  
Glial Reactivity

Endocannabinoids (eCB) are lipid-based neurotransmitters that are known to influence synaptic function in the visual system. eCBs are also known to suppress neuroinflammation in different pathological states. However, nothing is known about the roles of the eCB system during reprogramming of Müller glia (MG) into proliferating progenitor-like cells in the retina. Accordingly, we used the chick and mouse model to characterize expression patterns of eCB-related genes and applied pharmacological agents to examine how the eCB system impacts glial reactivity and the capacity of MG to become Müller glia-derived progenitor cells (MGPCs). We probed single cell RNA-seq libraries to identify eCB-related genes and identify cells with dynamic patterns of expression in damaged retinas. MG and inner retinal neurons expressed the eCB receptor CNR1, as well as enzymes involved in eCB metabolism. In the chick, intraocular injections of 2-Arachidonoylglycerol (2-AG) and Anandamide (AEA) potentiated the formation of MGPCs. Consistent with these findings, CNR1-agonists and MGLL-inhibitor promoted reprogramming, whereas CNR1-antagonist and inhibitors of eCB synthesis suppressed reprogramming. Surprisingly, retinal microglia were largely unaffected by increases or decreases in eCB signaling in both chick and mouse models. However, eCB-signaling suppressed the activation of NFkB-reporter in MG in damaged mouse retinas. We conclude that the eCB system in the retina influences the reactivity of MG and is important for regulating glial reactivity and the reprogramming of MG into proliferating MGPCs, but not for regulating the reactivity of immune cells in the retina.

scholarly journals Cellular Signaling in Müller Glia: Progenitor Cells for Regenerative and Neuroprotective Responses in Pharmacological Models of Retinal Degeneration

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yang Liu ◽  
Chenguang Wang ◽  
Guanfang Su
Keyword(s):  
Stem Cells ◽  
Visual Impairment ◽  
Therapeutic Strategy ◽  
Vision Loss ◽  
Muller Glia ◽  
Degenerative Diseases ◽  
Müller Glia ◽  
Cellular Source ◽  
Transduction Mechanisms ◽  
Retinal Degenerative Diseases

Retinal degenerative diseases are a leading cause of visual impairment or blindness. There are many therapies for delaying the progression of vision loss but no curative strategies currently. Stimulating intrinsic neuronal regeneration is a potential approach to therapy in retinal degenerative diseases. In contrast to stem cells, as embryonic/pluripotent stem cell-derived retinal progenitor cell or mesenchymal stem cells, Müller glia provided an endogenous cellular source for regenerative therapy in the retina. Müller glia are a major component of the retina and considerable evidence suggested these cells can be induced to produce the lost neurons in several species. Understanding the specific characteristic of Müller glia to generate lost neurons will inspire an attractive and alternative therapeutic strategy for treating visual impairment with regenerative research. This review briefly provides the different signal transduction mechanisms which are underlying Müller cell-mediated neuroprotection and neuron regeneration and discusses recent advances about regeneration from Müller glia-derived progenitors.

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