ISDN2012_0199: Lhx2 is required for the specification and differentiation of retinal Müller glia while also promoting formation of wide‐field amacrine cells

2012 ◽  
Vol 30 (8) ◽  
pp. 678-678
Author(s):  
J. Melo ◽  
S. Blackshaw
Keyword(s):  
Amacrine Cells ◽  
Wide Field ◽  
Muller Glia ◽  
Müller Glia

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 A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

2020 ◽  
Author(s):  
William N Grimes ◽  
Didem Göz Aytürk ◽  
Mrinalini Hoon ◽  
Takeshi Yoshimatsu ◽  
Clare Gamlin ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Glial Cells ◽  
Amacrine Cell ◽  
Electrical Coupling ◽  
Amacrine Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Type ◽  
Mammalian Retina ◽  
Ganglion Neurons

AbstractAmacrine cells are interneurons comprising the most diverse cell type in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, neurovascular control and metabolic regulation. Here, we report that a previously poorly characterized, but relatively abundant, inhibitory amacrine cell type in the mouse retina is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed extensive associations with Müller glia, whose processes often completely ensheathe the neurites of this amacrine cell type. Microinjections of small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name “Müller glia-coupled amacrine cell” or MAC. Our electrophysiological data also indicate that MACs release glycine at conventional chemical synapses with amacrine, bipolar and retinal ganglion cells (RGCs), and viral transsynaptic tracing showed connections to several known RGC types. Visually-evoked responses revealed a strong preference for light increments; these “ON” responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling to other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance StatementGap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system, and play a myriad of roles including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells are rare and poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia.

scholarly journals Retinal morphology in Astyanax mexicanus during degeneration

2019 ◽  
Author(s):  
Amany Emam ◽  
Marina Yoffe ◽  
Henry Cardona ◽  
Daphne Soares
Keyword(s):  
Retinitis Pigmentosa ◽  
Amacrine Cells ◽  
Cell Types ◽  
Retinal Diseases ◽  
Muller Glia ◽  
Müller Glia ◽  
Astyanax Mexicanus ◽  
Outer Segments

AbstractThe teleost Astyanax mexicanus is extant in two readily available forms. One that lives in Mexican rivers and various convergent forms that live in nearby caves. These fish are born with eyes but in the cavefish they degenerate during development. It is known that the lens of cavefish undergoes apoptosis and that some cells in the neuroretina also die. It has not been described, however, if glia and various components of the neuroretina form before complete eye degeneration. Here we examined the development of the retina of the closest living ancestor that lives in the rivers and members of two lineages of cavefish. We report that although the neuroretina is smaller and more compact, it has all cell types and layers including amacrine cells and Muller glia. While various makers for photoreceptors are present in the cavefish inner segments, the outer segments of the photoreceptors in cavefish are missing from the earliest stages examined. This shows that the machinery for visual transducing discs might still be present but not organized in one part of the cell. It is interesting to note that the deficiencies in Astyanax cavefish resemble retinal diseases, such as retinitis pigmentosa.

scholarly journals Generation of human neural retina transcriptome atlas by single cell RNA sequencing

2018 ◽  
Author(s):  
Samuel W. Lukowski ◽  
Camden Y. Lo ◽  
Alexei Sharov ◽  
Quan H. Nguyen ◽  
Lyujie Fang ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Amacrine Cells ◽  
Cell Types ◽  
Muller Glia ◽  
Müller Glia ◽  
Cone Photoreceptors ◽  
Rod Photoreceptors ◽  
Retinal Cells ◽  
Single Cell Rna Sequencing

SummaryThe retina is a highly specialized neural tissue that senses light and initiates image processing. Although the functional organisation of specific cells within the retina has been well-studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile cell types in the human retina, we performed single cell RNA-sequencing on 20,009 cells obtained post-mortem from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct clusters representing all known retinal cells: rod photoreceptors, cone photoreceptors, Müller glia cells, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, retinal astrocytes and microglia. Notably, our data captured molecular profiles for healthy and early degenerating rod photoreceptors, and revealed a novel role of MALAT1 in putative rod degeneration. We also demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to our understanding of retinal biology and disease.

scholarly journals Evidence of Müller glia conversion into retina ganglion cells using Neurogenin2

2018 ◽  
Author(s):  
Roberta Pereira de Melo Guimarães ◽  
Bruna Soares Landeira ◽  
Diego Marques Coelho ◽  
Daiane Cristina Ferreira Golbert ◽  
Mariana S. Silveira ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Amacrine Cells ◽  
The Elderly ◽  
Retinal Cell ◽  
Muller Glia ◽  
Müller Glia ◽  
Neuronal Genes ◽  
Consistent Increase ◽  
Induced Neurons

AbstractMacular Degeneration, Glaucoma, and Retinitis Pigmentosa are all leading causes of irreversible visual impairment in the elderly, affecting hundreds of millions of patients. Müller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume proliferation in the adult injured retina and contribute to tissue repair. Also, MGC can be genetically reprogrammed through the expression of the transcription factor (TF) Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient to lineage-reprogram MGC into iNs. The efficiency of MGC lineage conversion by NEUROG2 is similar to that observed after expression of ASCL1. However, reprogramming efficiency is affected by previous exposure to EGF and FGF2 during the expansion of MGC population. Transduction of either Neurog2 or Ascl1 led to the upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) genes. In vivo electroporation of Neurog2 in the neonatal retina also induced a shift in the generation of retinal cell subtypes, favoring the differentiation RGCs at the expense of MGCs. Altogether, our data indicate that Neurog2 induces lineage conversion of MGCs into RGC-like iNs.

scholarly journals Develop an efficient and specific AAV-based labeling system for Muller glia in mice

2021 ◽  
Author(s):  
Yanxia Gao ◽  
Kailun Fang ◽  
Zixiang Yan ◽  
Haiwei Zhang ◽  
Guannan Geng ◽  
...  
Keyword(s):  
Cell Fate ◽  
Vision Loss ◽  
Hepatitis Virus ◽  
Regulatory Element ◽  
Amacrine Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Reporter System ◽  
Cell Degeneration ◽  
Labeling System

AbstractCell degeneration in the retina leads to several ocular diseases and vision loss. Considerable research efforts focus on reprogramming Muller glia (MG) into functional cells to rescue vision as a promising therapeutic strategy, although whether MG can convert into functional amacrine cells, bipolar cells, retinal ganglia cells (RGCs), rods or cones in mammals remains controversial. The broad applicability of tracking MG differentiation thus presents a need for improved labeling efficiency and specificity. Here, we compared AAV-based labeling strategies with conventional lineage-tracking by crossing transgenic mouse lines. We found that reporter expression was weak and not MG-specific in mGFAP-Cre transgenic mice. Different AAV serotypes showed a range of efficiency and specificity in labeling MG, leading us to optimize a human GFAP-Cre reporter system packaged in the AAV9 serotype with the WPRE (WPRE, woodchuck hepatitis virus post-transcriptional regulatory element) removed. The hGFAP-Cre-ΔWPRE reporter could label 20-73.8% MGs, with non-specific RGC labeling rates ranging from 0-0.08% at doses of 1 × 108 to 1010 vector genomes (vg) per eye, an approximate 40-fold reduction compared with the AAV9-hGFAP-Cre-WPRE labeling system. The AAV9-hGFAP-Cre-ΔWPRE system thus represents a highly efficient and specific labeling system for Muller glia, providing a valuable tool for tracking cell fate in vivo.

Müller Glia-Mediated Retinal Regeneration

2021 ◽  
Author(s):  
Hui Gao ◽  
Luodan A ◽  
Xiaona Huang ◽  
Xi Chen ◽  
Haiwei Xu
Keyword(s):  
Muller Glia ◽  
Müller Glia ◽  
Retinal Regeneration
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