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Vsx2 in the zebrafish retina: restricted lineages through derepression.

Vitorino M, Jusuf PR, Maurus D, Kimura Y, Higashijima S, Harris WA - Neural Dev (2009)

Bottom Line: Vsx2 is a repressor whose targets include transcription factors such as Vsx1, which is expressed in the progenitors of distinct non-Vsx2 bipolars, and the basic helix-loop-helix transcription factor Ath5, which restricts the fate of progenitors to retinal ganglion cells, horizontal cells, amacrine cells and photoreceptors fates.Foxn4, expressed in the progenitors of amacrine and horizontal cells, is also negatively regulated by Vsx2.Our data thus suggest Vsx2-positive RPCs are fully multipotent retinal progenitors and that when Vsx2 is downregulated, Vsx2-negative progenitors escape Vsx2 repression and so are able to express factors that restrict lineage potential.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK. mspdcv2@cam.ac.uk

ABSTRACT

Background: The neurons in the vertebrate retina arise from multipotent retinal progenitor cells (RPCs). It is not clear, however, which progenitors are multipotent or why they are multipotent.

Results: In this study we show that the homeodomain transcription factor Vsx2 is initially expressed throughout the retinal epithelium, but later it is downregulated in all but a minor population of bipolar cells and all Müller glia. The Vsx2-negative daughters of Vsx2-positive RPCs divide and give rise to all other cell types in the retina. Vsx2 is a repressor whose targets include transcription factors such as Vsx1, which is expressed in the progenitors of distinct non-Vsx2 bipolars, and the basic helix-loop-helix transcription factor Ath5, which restricts the fate of progenitors to retinal ganglion cells, horizontal cells, amacrine cells and photoreceptors fates. Foxn4, expressed in the progenitors of amacrine and horizontal cells, is also negatively regulated by Vsx2.

Conclusion: Our data thus suggest Vsx2-positive RPCs are fully multipotent retinal progenitors and that when Vsx2 is downregulated, Vsx2-negative progenitors escape Vsx2 repression and so are able to express factors that restrict lineage potential.

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Vsx2 versus Vsx1 arise from distinct lineages. Time-lapse images from Additional file 2 showing cells transplanted from Tg(vsx1:GFP; vsx2:dsRed) into wild type to reveal individual cell morphology. Vsx1:GFP progenitors that have already lost Vsx2:DsRed (green only) or are in the process of (weak red signal remaining in these green cells) downregulating Vsx2:DsRed divide apically (white arrowheads). They upregulate Vsx1:GFP (green arrows) and differentiate as a group of bipolar cells. Vsx2:DsRed is expressed at a low level initially. It fades in cells that turn on Vsx1:GFP, but the red signal also fades during the movie shown in Additional file 2 due to bleaching, so Vsx2:DsRed progenitors cannot be followed throughout the entire movie. Vsx2:DsRed is later dramatically upregulated in cells that do not express Vsx1 (red arrows). Scale bar: 20 μm.
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Figure 5: Vsx2 versus Vsx1 arise from distinct lineages. Time-lapse images from Additional file 2 showing cells transplanted from Tg(vsx1:GFP; vsx2:dsRed) into wild type to reveal individual cell morphology. Vsx1:GFP progenitors that have already lost Vsx2:DsRed (green only) or are in the process of (weak red signal remaining in these green cells) downregulating Vsx2:DsRed divide apically (white arrowheads). They upregulate Vsx1:GFP (green arrows) and differentiate as a group of bipolar cells. Vsx2:DsRed is expressed at a low level initially. It fades in cells that turn on Vsx1:GFP, but the red signal also fades during the movie shown in Additional file 2 due to bleaching, so Vsx2:DsRed progenitors cannot be followed throughout the entire movie. Vsx2:DsRed is later dramatically upregulated in cells that do not express Vsx1 (red arrows). Scale bar: 20 μm.

Mentions: To investigate how these two bipolar populations are generated, we made time-lapse movies on transgenic embryos. Vsx2-positive bipolar cells were seen to arise from Vsx2-positive progenitors (Figure 2; Additional file 1). After the last division of such a progenitor, Vsx2:GFP expression increases dramatically as the bipolar cells move to their final position in the INL and begin to differentiate. In double transgenic embryos, Tg(vsx2:dsRed;vsx1:GFP), red 'Vsx2-positive' bipolar cells generally arise from progenitors that are 'Vsx1-negative', that is, not green (Figure 5; Additional file 2). Vsx1 expressing bipolar cells, however, initially arise from progenitors that express Vsx2 (Figure 6). However, as soon as Vsx1 expression begins in these progenitors, Vsx2 expression decreases (Figure 6; Additional file 3). Some, and perhaps all, of these Vsx1-positive, Vsx2-negative cells go through at least one round of mitosis before they differentiate (Figures 5 and 6; Additional files 2 and 3). Thus, Vsx2 bipolar cells arise from Vsx2+/Vsx1- progenitors. In contrast, Vsx1-positive progenitors that have downregulated Vsx2 divide to produce Vsx1-positive bipolar cells.


Vsx2 in the zebrafish retina: restricted lineages through derepression.

Vitorino M, Jusuf PR, Maurus D, Kimura Y, Higashijima S, Harris WA - Neural Dev (2009)

Vsx2 versus Vsx1 arise from distinct lineages. Time-lapse images from Additional file 2 showing cells transplanted from Tg(vsx1:GFP; vsx2:dsRed) into wild type to reveal individual cell morphology. Vsx1:GFP progenitors that have already lost Vsx2:DsRed (green only) or are in the process of (weak red signal remaining in these green cells) downregulating Vsx2:DsRed divide apically (white arrowheads). They upregulate Vsx1:GFP (green arrows) and differentiate as a group of bipolar cells. Vsx2:DsRed is expressed at a low level initially. It fades in cells that turn on Vsx1:GFP, but the red signal also fades during the movie shown in Additional file 2 due to bleaching, so Vsx2:DsRed progenitors cannot be followed throughout the entire movie. Vsx2:DsRed is later dramatically upregulated in cells that do not express Vsx1 (red arrows). Scale bar: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683830&req=5

Figure 5: Vsx2 versus Vsx1 arise from distinct lineages. Time-lapse images from Additional file 2 showing cells transplanted from Tg(vsx1:GFP; vsx2:dsRed) into wild type to reveal individual cell morphology. Vsx1:GFP progenitors that have already lost Vsx2:DsRed (green only) or are in the process of (weak red signal remaining in these green cells) downregulating Vsx2:DsRed divide apically (white arrowheads). They upregulate Vsx1:GFP (green arrows) and differentiate as a group of bipolar cells. Vsx2:DsRed is expressed at a low level initially. It fades in cells that turn on Vsx1:GFP, but the red signal also fades during the movie shown in Additional file 2 due to bleaching, so Vsx2:DsRed progenitors cannot be followed throughout the entire movie. Vsx2:DsRed is later dramatically upregulated in cells that do not express Vsx1 (red arrows). Scale bar: 20 μm.
Mentions: To investigate how these two bipolar populations are generated, we made time-lapse movies on transgenic embryos. Vsx2-positive bipolar cells were seen to arise from Vsx2-positive progenitors (Figure 2; Additional file 1). After the last division of such a progenitor, Vsx2:GFP expression increases dramatically as the bipolar cells move to their final position in the INL and begin to differentiate. In double transgenic embryos, Tg(vsx2:dsRed;vsx1:GFP), red 'Vsx2-positive' bipolar cells generally arise from progenitors that are 'Vsx1-negative', that is, not green (Figure 5; Additional file 2). Vsx1 expressing bipolar cells, however, initially arise from progenitors that express Vsx2 (Figure 6). However, as soon as Vsx1 expression begins in these progenitors, Vsx2 expression decreases (Figure 6; Additional file 3). Some, and perhaps all, of these Vsx1-positive, Vsx2-negative cells go through at least one round of mitosis before they differentiate (Figures 5 and 6; Additional files 2 and 3). Thus, Vsx2 bipolar cells arise from Vsx2+/Vsx1- progenitors. In contrast, Vsx1-positive progenitors that have downregulated Vsx2 divide to produce Vsx1-positive bipolar cells.

Bottom Line: Vsx2 is a repressor whose targets include transcription factors such as Vsx1, which is expressed in the progenitors of distinct non-Vsx2 bipolars, and the basic helix-loop-helix transcription factor Ath5, which restricts the fate of progenitors to retinal ganglion cells, horizontal cells, amacrine cells and photoreceptors fates.Foxn4, expressed in the progenitors of amacrine and horizontal cells, is also negatively regulated by Vsx2.Our data thus suggest Vsx2-positive RPCs are fully multipotent retinal progenitors and that when Vsx2 is downregulated, Vsx2-negative progenitors escape Vsx2 repression and so are able to express factors that restrict lineage potential.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK. mspdcv2@cam.ac.uk

ABSTRACT

Background: The neurons in the vertebrate retina arise from multipotent retinal progenitor cells (RPCs). It is not clear, however, which progenitors are multipotent or why they are multipotent.

Results: In this study we show that the homeodomain transcription factor Vsx2 is initially expressed throughout the retinal epithelium, but later it is downregulated in all but a minor population of bipolar cells and all Müller glia. The Vsx2-negative daughters of Vsx2-positive RPCs divide and give rise to all other cell types in the retina. Vsx2 is a repressor whose targets include transcription factors such as Vsx1, which is expressed in the progenitors of distinct non-Vsx2 bipolars, and the basic helix-loop-helix transcription factor Ath5, which restricts the fate of progenitors to retinal ganglion cells, horizontal cells, amacrine cells and photoreceptors fates. Foxn4, expressed in the progenitors of amacrine and horizontal cells, is also negatively regulated by Vsx2.

Conclusion: Our data thus suggest Vsx2-positive RPCs are fully multipotent retinal progenitors and that when Vsx2 is downregulated, Vsx2-negative progenitors escape Vsx2 repression and so are able to express factors that restrict lineage potential.

Show MeSH
Related in: MedlinePlus