scholarly journals Transcriptional logic of cell fate specification and axon guidance in early born retinal neurons revealed by single-cell mRNA profiling

2018 ◽  
Author(s):  
Quentin Lo Giudice ◽  
Marion Leleu ◽  
Pierre J. Fabre
Keyword(s):  
Axon Guidance ◽  
Cell Fate ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Retinal Ganglion ◽  
Cell Fate Specification ◽  
Retinal Neurons ◽  
Fate Specification ◽  
Guidance Cues ◽  
Insight Into

ABSTRACTRetinal ganglion cells (RGC), together with cone photoreceptors, horizontal cells (HC) and amacrine cells (AC), are the first classes of neurons produced in the retina. Here we have profiled 5348 single retinal cells and provided a comprehensive transcriptomic atlas showing the broad diversity of the developing retina at the time when the four early-born cells are being produced. Our results show the transcriptional sequences that establish the hierarchical ordering of early cell fate specification in the retina. RGC maturation follows six waves of gene expression, giving new insight into the regulatory logic of RGC differentiation. Early-generated RGCs transcribe an increasing amount of guidance cues for young peripheral RGC axons that express the matching receptors. Finally, spatial signatures in sub-populations of RGCs allowed to define novel molecular markers that are spatially restricted during the development of the retina. Altogether this study is a valuable resource that identifies new players in mouse retinal development, shedding light on transcription factors sequence and guidance cues dynamics in space and time.

scholarly journals Single-cell transcriptional logic of cell-fate specification and axon guidance in early-born retinal neurons

Development ◽  
2019 ◽  
Vol 146 (17) ◽  
pp. dev178103 ◽  
Author(s):  
Quentin Lo Giudice ◽  
Marion Leleu ◽  
Gioele La Manno ◽  
Pierre J. Fabre
Keyword(s):  
Axon Guidance ◽  
Single Cell ◽  
Cell Fate ◽  
Cell Fate Specification ◽  
Retinal Neurons ◽  
Fate Specification

scholarly journals Pax6 modulates intra-retinal axon guidance and fasciculation of retinal ganglion cells during retinogenesis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Soundararajan Lalitha ◽  
Budhaditya Basu ◽  
Suresh Surya ◽  
Vadakkath Meera ◽  
Paul Ann Riya ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Ganglion Cells ◽  
Transcriptome Profiling ◽  
Retinal Ganglion ◽  
Temporal Expression ◽  
Fate Specification ◽  
Extracellular Matrix Molecules ◽  
Coordinated Expression ◽  
Spatio Temporal ◽  
Retinal Axon

Abstract Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master regulator gene, has a spatio-temporal expression typically restricted till neurogenesis and fate-specification. However, our observation of persistent expression of Pax6 in mature RGCs led us to hypothesize that Pax6 could play a major role in axon guidance after fate specification. Here, we found significant alteration in intra-retinal axon guidance and fasciculation upon knocking out of Pax6 in E15.5 retina. Through unbiased transcriptome profiling between Pax6fl/fl and Pax6−/− retinas, we revealed the mechanistic insight of its role in axon guidance. Our results showed a significant increase in the expression of extracellular matrix molecules and decreased expression of retinal fate specification and neuron projection guidance molecules. Additionally, we found that EphB1 and Sema5B are directly regulated by Pax6 owing to the guidance defects and improper fasciculation of axons. We conclude that Pax6 expression post fate specification of RGCs is necessary for regulating the expression of axon guidance genes and most importantly for maintaining a conducive ECM through which the nascent axons get guided and fasciculate to reach the optic disc.

scholarly journals Tbr2-expressing retinal ganglion cells are ipRGCs

2020 ◽  
Author(s):  
Chai-An Mao ◽  
Ching-Kang Chen ◽  
Takae Kiyama ◽  
Nicole Weber ◽  
Christopher M. Whitaker ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Primary Component ◽  
Retinal Ganglion ◽  
Retinal Neurons ◽  
T Box ◽  
Retinofugal Projections ◽  
A Minor

AbstractThe mammalian retina contains more than 40 retinal ganglion cell (RGC) subtypes based on their unique morphologies, functions, and molecular profiles. Among them, intrinsically photosensitive RGCs (ipRGCs) are the first specified RGC type that emerged from a common pool of retinal progenitor cells. Previous work has shown that T-box transcription factor T-brain 2 (Tbr2) is essential for the formation and maintenance of ipRGCs, and Tbr2-expressing RGCs activate Opn4 expression upon native ipRGC loss, suggesting that Tbr2+ RGCs can serve as a reservoir for ipRGCs. However, the identity of Tbr2+ RGCs has not been fully vetted, and the developmental and molecular mechanisms underlying the formation of native and reservoir ipRGCs remain unclear. Here, we showed that Tbr2-expressing retinal neurons include RGCs and GABAergic displaced amacrine cells (dACs). Using genetic sparse labeling, we demonstrated that the majority of Tbr2+ RGCs are intrinsically photosensitive and morphologically indistinguishable from known ipRGC types and have identical retinofugal projections. Additionally, we found a minor fraction of Pou4f1-expressing Tbr2+ RGCs marks a unique OFF RGC subtype. Most of the Tbr2+ RGCs can be ablated by anti-melanopsin-SAP toxin in adult retinas, supporting that Tbr2+ RGCs contain reservoir ipRGCs that express melanopsin at varying levels. When Tbr2 is deleted in adult retinas, Opn4 expression is diminished followed by the death of Tbr2-deficient cells, suggesting that Tbr2 is essential for both Opn4 expression and ipRGC survival. Finally, Tbr2 extensively occupies multiple T-elements in the Opn4 locus, indicating a direct regulatory role for Tbr2 on Opn4 transcription.Significance statementMelanopsin/Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) play fundamental roles in non-image forming vision. Previously we identified Tbr2 as the key transcription regulator for the development and maintenance of ipRGCs. To reveal the full identity of Tbr2-expressing retinal neurons and how Tbr2 acts, we generated a novel mouse line to genetically label and study Tbr2-expressing cells. Our in-depth characterizations firmly established that most Tbr2+ RGCs are indeed ipRGCs and that Tbr2 regulates Opn4 transcription, thus place Tbr2-Opn4 transcription regulatory hierarchy as the primary component in the development and maintenance of the non-image forming visual system.

Evidence of functional long-range Wnt/Wg in the developing Drosophila wing epithelium

2018 ◽  
Author(s):  
Varun Chaudhary ◽  
Michael Boutros
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Gene ◽  
Secreted Proteins ◽  
Cell Fate Specification ◽  
Wild Type ◽  
Fate Specification ◽  
Drosophila Wing ◽  
Wnt Proteins ◽  
Insight Into

SUMMARYWnts are secreted proteins that regulate cell fate specification during development of all metazoans. Wnt proteins were proposed to spread over several cell diameters to activate signalling directly at a distance. In the Drosophila wing epithelium, an extracellular gradient of Wingless (Wg, the homolog of Wnt1) was observed extending over several cells away from producing cells. However, it was also recently shown that a membrane-tethered Neurotactin-Wg fusion protein (NRT-Wg) can rescue the loss-of endogenous Wg, leading to proper patterning of the wing. Therefore, whether Wg spreading is required for correct tissue patterning during development remains controversial and the functional range of wild-type Wg is unclear. Here, by capturing secreted Wg on distally located cells we show that the Wg gradient acts directly up to eleven cell distances. Cells located outside the reach of extracellular Wg depend on the Frizzled2 receptor to maintain target gene expression. We find that NRT-Wg is not restricted to the producing cells and propose that it can rescue signalling defects by perdurance in the receiving cells. These results provide insight into the mechanisms by which Wnt proteins mediate patterning of a rapidly growing tissue.

Sox proteins: regulators of cell fate specification and differentiation

Development ◽  
2013 ◽  
Vol 140 (20) ◽  
pp. 4129-4144 ◽  
Author(s):  
Y. Kamachi ◽  
H. Kondoh
Keyword(s):  
Cell Fate ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Sox Proteins

scholarly journals GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells

2018 ◽  
Vol 115 (51) ◽  
pp. E12083-E12090 ◽  
Author(s):  
Adam Bleckert ◽  
Chi Zhang ◽  
Maxwell H. Turner ◽  
David Koren ◽  
David M. Berson ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Selective Reduction ◽  
Amacrine Cells ◽  
Gaba Release ◽  
Direction Selectivity ◽  
Inhibitory Synapses ◽  
Retinal Ganglion ◽  
Gabaergic Transmission ◽  
Starburst Amacrine Cells ◽  
Receptor Clusters

Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.

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