scholarly journals Genetic interplay between transcription factor Pou4f1/Brn3a and neurotrophin receptor Ret in retinal ganglion cell type specification

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Vladimir Vladimirovich Muzyka ◽  
Tudor Constantin Badea
Keyword(s):  
Transcription Factor ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Gene Dosage ◽  
Neurotrophin Receptor ◽  
Surrounding Tissue ◽  
Retinal Ganglion ◽  
Cell Fate Decisions ◽  
Type Specification

Abstract Background While the transcriptional code governing retinal ganglion cell (RGC) type specification begins to be understood, its interplay with neurotrophic signaling is largely unexplored. In mice, the transcription factor Brn3a/Pou4f1 is expressed in most RGCs, and is required for the specification of RGCs with small dendritic arbors. The Glial Derived Neurotrophic Factor (GDNF) receptor Ret is expressed in a subset of RGCs, including some expressing Brn3a, but its role in RGC development is not defined. Methods Here we use combinatorial genetic experiments using conditional knock-in reporter alleles at the Brn3a and Ret loci, in combination with retina- or Ret specific Cre drivers, to generate complete or mosaic genetic ablations of either Brn3a or Ret in RGCs. We then use sparse labelling to investigate Brn3a and Ret gene dosage effects on RGC dendritic arbor morphology. In addition, we use immunostaining and/or gene expression profiling by RNASeq to identify transcriptional targets relevant for the potential Brn3a-Ret interaction in RGC development. Results We find that mosaic gene dosage manipulation of the transcription factor Brn3a/Pou4f1 in neurotrophic receptor Ret heterozygote RGCs results in altered cell fate decisions and/or morphological dendritic defects. Specific RGC types are lost if Brn3a is ablated during embryogenesis and only mildly affected by postnatal Brn3a ablation. Sparse but not complete Brn3a heterozygosity combined with complete Ret heterozygosity has striking effects on RGC type distribution. Brn3a only mildly modulates Ret transcription, while Ret knockouts exhibit slightly skewed Brn3a and Brn3b expression during development that is corrected by adult age. Brn3a loss of function modestly but significantly affects distribution of Ret co-receptors GFRα1-3, and neurotrophin receptors TrkA and TrkC in RGCs. Conclusions Based on these observations, we propose that Brn3a and Ret converge onto developmental pathways that control RGC type specification, potentially through a competitive mechanism requiring signaling from the surrounding tissue.

scholarly journals Genetic Interplay Between Transcription Factor Pou4f1/Brn3a and Neurotrophin Receptor Ret In Retinal Ganglion Cell Type Specification

2020 ◽  
Author(s):  
Vladimir Vladimirovich Muzyka ◽  
Tudor Constantin Badea
Keyword(s):  
Transcription Factor ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Gene Dosage ◽  
Neurotrophin Receptor ◽  
Surrounding Tissue ◽  
Retinal Ganglion ◽  
Cell Fate Decisions ◽  
Type Specification

AbstractWhile the transcriptional code governing retinal ganglion cell (RGC) type specification begins to be understood, its interplay with neurotrophic signaling is largely unexplored. Using sparse random recombination, we show that mosaic gene dosage manipulation of the transcription factor Brn3a/Pou4f1 in neurotrophic receptor Ret heterozygote RGCs results in altered cell fate decisions and/or morphological dendritic defects. Specific RGC types are lost if Brn3a is ablated during embryogenesis and only mildly affected by postnatal Brn3a ablation. Sparse but not complete Brn3a heterozygosity combined with complete Ret heterozygosity has striking effects on RGC type distribution. Brn3a only mildly modulates Ret transcription, while Ret knockouts exhibit normal Brn3a and Brn3b expression. However, Brn3a loss of function significantly affects distribution of Ret co-receptors GFRα1-3, and neurotrophin receptors TrkA and TrkC in RGCs. Based on these observations, we propose that Brn3a and Ret converge onto developmental pathways that control RGC type specification, potentially through a competitive mechanism requiring signaling from the surrounding tissue.

scholarly journals Retinal Stem Cells Transplanted into Models of Late Stages of Retinitis Pigmentosa Preferentially Adopt a Glial or a Retinal Ganglion Cell Fate

2007 ◽  
Vol 48 (1) ◽  
pp. 446 ◽  
Author(s):  
Kriss Canola ◽  
Brigitte Ange´nieux ◽  
Meriem Tekaya ◽  
Alexander Quiambao ◽  
Muna I. Naash ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinitis Pigmentosa ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Retinal Ganglion ◽  
Late Stages ◽  
Retinal Stem Cells

scholarly journals Genetic Interactions between Brn3 Transcription Factors in Retinal Ganglion Cell Type Specification

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e76347 ◽  
Author(s):  
Melody Shi ◽  
Sumit R. Kumar ◽  
Oluwaseyi Motajo ◽  
Friedrich Kretschmer ◽  
Xiuqian Mu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Genetic Interactions ◽  
Retinal Ganglion ◽  
Cell Type ◽  
Type Specification

Immunoregulation of retinal ganglion cell fate in glaucoma

2009 ◽  
Vol 88 (4) ◽  
pp. 825-830 ◽  
Author(s):  
Martin B. Wax ◽  
Gülgün Tezel
Keyword(s):  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Retinal Ganglion

scholarly journals Multifactorial Pathogenic Processes of Retinal Ganglion Cell Degeneration in Glaucoma towards Multi-Target Strategies for Broader Treatment Effects

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1372
Author(s):  
Gülgün Tezel
Keyword(s):  
Neurodegenerative Disease ◽  
Ganglion Cell ◽  
Cell Fate ◽  
Retinal Ganglion Cell ◽  
Inflammatory Responses ◽  
Treatment Strategies ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Broad Perspective ◽  
Proinflammatory Mediators

Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cell (RGC) somas, degeneration of axons, and loss of synapses at dendrites and axon terminals. Glaucomatous neurodegeneration encompasses multiple triggers, multiple cell types, and multiple molecular pathways through the etiological paths with biomechanical, vascular, metabolic, oxidative, and inflammatory components. As much as intrinsic responses of RGCs themselves, divergent responses and intricate interactions of the surrounding glia also play decisive roles for the cell fate. Seen from a broad perspective, multitarget treatment strategies have a compelling pathophysiological basis to more efficiently manipulate multiple pathogenic processes at multiple injury sites in such a multifactorial neurodegenerative disease. Despite distinct molecular programs for somatic and axonal degeneration, mitochondrial dysfunction and glia-driven neuroinflammation present interdependent processes with widespread impacts in the glaucomatous retina and optic nerve. Since dysfunctional mitochondria stimulate inflammatory responses and proinflammatory mediators impair mitochondria, mitochondrial restoration may be immunomodulatory, while anti-inflammatory treatments protect mitochondria. Manipulation of these converging routes may thus allow a unified treatment strategy to protect RGC axons, somas, and synapses. This review presents an overview of recent research advancements with emphasis on potential treatment targets to achieve the best treatment efficacy to preserve visual function in glaucoma.

scholarly journals Identification of Retinal Ganglion Cell Types and Brain Nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock-in allele

2020 ◽  
Author(s):  
Nadia Parmhans ◽  
Anne Drury Fuller ◽  
Eileen Nguyen ◽  
Katherine Chuang ◽  
David Swygart ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Visual Information ◽  
Cell Types ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Retinal Ganglion ◽  
Brain Nuclei ◽  
The Brain

AbstractMembers of the POU4F/Brn3 transcription factor family have an established role in the development of retinal ganglion cell types (RGCs), the projection sensory neuron conveying visual information from the mammalian eye to the brain. Our previous work using sparse random recombination of a conditional knock-in reporter allele expressing Alkaline Phosphatase (AP) and intersectional genetics had identified three types of Pou4f3/Brn3c positive (Brn3c+) RGCs. Here, we describe a novel Brn3cCre mouse allele generated by serial Dre to Cre recombination. We use this allele to explore the expression overlap of Brn3c with Brn3a and Brn3b and the dendritic arbor morphologies and visual stimulus properties of Brn3c+ RGC types. Furthermore, we explore Brn3c-expressing brain nuclei. Our analysis reveals a much larger number of Brn3c+ RGCs and more diverse set of RGC types than previously reported. The majority of RGCs having expressed Brn3c during development are still Brn3c positive in the adult, and all of them express Brn3a while only about half express Brn3b. Intersection of Brn3b and Brn3c expression highlights an area of increased RGC density, similar to an area centralis, corresponding to part of the binocular field of view of the mouse. Brn3c+ neurons and projections are present in multiple brain nuclei. Brn3c+ RGC projections can be detected in the Lateral Geniculate Nucleus (LGN), Pretectal Area (PTA) and Superior Colliculus (SC) but also in the thalamic reticular nucleus (TRN), a visual circuit station that was not previously described to receive retinal input. Most Brn3c+ neurons of the brain are confined to the pretectum and the dorsal midbrain. Amongst theses we identify a previously unknown Brn3c+ subdivision of the deep mesencephalic nucleus (DpMe). Thus, our newly generated allele provides novel biological insights into RGC type classification, brain connectivity and midbrain cytoarchitectonic, and opens the avenue for specific characterization and manipulation of these structures.

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