Serotonin released from amacrine neurons is scavenged and degraded in bipolar neurons in the retina

Ghai, Kanika; Zelinka, Christopher; Fischer, Andy J.

doi:10.1111/j.1471-4159.2009.06270.x

Cited by 56 publications

(54 citation statements)

References 40 publications

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“…Similar to previous studies (Fischer et al, 2009a(Fischer et al, ,b, 2010Ghai et al, 2009), immunofluorescence was quantified using ImagePro 6.2 (Media Cybernetics). The mean area, intensity and density sum was calculated for the pixels within threshold regions from at least four different retinas for each experimental condition.…”

Section: Photography Cell Counts and Statisticsmentioning

confidence: 99%

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Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

2014

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Identification of the signaling pathways that influence the reprogramming of Müller glia into neurogenic retinal progenitors is key to harnessing the potential of these cells to regenerate the retina. Glucocorticoid receptor (GCR) signaling is commonly associated with anti-inflammatory responses and GCR agonists are widely used to treat inflammatory diseases of the eye, even though the cellular targets and mechanisms of action in the retina are not well understood. We find that signaling through GCR has a significant impact upon the ability of Müller glia to become proliferating Müller glia-derived progenitor cells (MGPCs). The primary amino acid sequence and pattern of GCR expression in the retina is highly conserved across vertebrate species, including chickens, mice, guinea pigs, dogs and humans. In all of these species we find GCR expressed by the Müller glia. In the chick retina, we find that GCR is expressed by progenitors in the circumferential marginal zone (CMZ) and is upregulated by Müller glia in acutely damaged retinas. Activation of GCR signaling inhibits the formation of MGPCs and antagonizes FGF2/MAPK signaling in the Müller glia. By contrast, we find that inhibition of GCR signaling stimulates the formation of proliferating MGPCs in damaged retinas, and enhances the neuronal differentiation while diminishing glial differentiation. Given the conserved expression pattern of GCR in different vertebrate retinas, we propose that the functions and mechanisms of GCR signaling are highly conserved and are mediated through the Müller glia. We conclude that GCR signaling directly inhibits the formation of MGPCs, at least in part, by interfering with FGF2/MAPK signaling.

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Section: Photography Cell Counts and Statisticsmentioning

confidence: 99%

“…Digital photomicroscopy was performed as described in previous studies (Fischer et al, 2008Ghai et al, 2009Ghai et al, , 2010. Similar to previous studies (Fischer et al, 2009a(Fischer et al, ,b, 2010Ghai et al, 2009), immunofluorescence was quantified using ImagePro 6.2 (Media Cybernetics).…”

Section: Photography Cell Counts and Statisticsmentioning

confidence: 99%

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

2014

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“…Similar to previous reports (Fischer et al, 2009bGhai et al, 2009), immunofluorescence was quantified using ImagePro 6.2 (Media Cybernetics). Identical illumination, microscope, and camera settings were used to obtain images for quantification.…”

Section: Microscopy Quantitative Immunofluorescence and Cell Countsmentioning

confidence: 99%

mTor-signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina

et al. 2016

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We investigate the roles of mTor signaling in the formation of Müller glia-derived progenitor cells (MGPCs) in the chick retina. During embryonic development, pS6 (a readout of active mTor signaling) is present in early-stage retinal progenitors, differentiating amacrine and ganglion cells, and late-stage progenitors or maturing Müller glia. By contrast, pS6 is present at low levels in a few scattered cell types in mature, healthy retina. Following retinal damage, in which MGPCs are known to form, mTor signaling is rapidly activated in Müller glia. Inhibition of mTor in damaged retinas prevented the accumulation of pS6 in Müller glia and reduced numbers of proliferating MGPCs. Inhibition of mTor had no effect on MAPK signaling or on upregulation of the stem cell factor Klf4, whereas Pax6 upregulation was significantly reduced. Inhibition of mTor potently blocked the MGPC-promoting effects of Hedgehog, Wnt and glucocorticoid signaling in damaged retinas. In the absence of retinal damage, insulin, IGF1 and FGF2 induced pS6 in Müller glia, and this was blocked by mTor inhibitor. In FGF2-treated retinas, in which MGPCs are known to form, inhibition of mTor blocked the accumulation of pS6, the upregulation of Pax6 and the formation of proliferating MGPCs. We conclude that mTor signaling is required, but not sufficient, to stimulate Müller glia to give rise to proliferating progenitors, and the network of signaling pathways that drive the formation of MGPCs requires activation of mTor.

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“…Digoxigenin-labeled riboprobes were synthesized using the DIG RNA Labeling Kit (Roche), and stored at −80°C until use. Eyes were dissected, fixed, sectioned and processed for in situ hybridization as described previously (Fischer et al, 2002a(Fischer et al, , 2004aGhai et al, 2009Ghai et al, , 2010.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Hedgehog-signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the retina

Todd

Fischer

2015

Development

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Müller glia can be stimulated to de-differentiate and become proliferating progenitor cells that regenerate neurons in the retina. The signaling pathways that regulate the formation of proliferating Müller glia-derived progenitor cells (MGPCs) are beginning to be revealed. The purpose of this study was to investigate whether Hedgehog (Hh) signaling influences the formation of MGPCs in the chick retina. We find that Hh signaling is increased in damaged retinas where MGPCs are known to form. Sonic Hedgehog (Shh) is normally present in the axons of ganglion cells, but becomes associated with Müller glia and MGPCs following retinal damage. Activation of Hh signaling with recombinant human SHH (rhShh) or smoothened agonist (SAG) increased levels of Ptch1, Gli1, Gli2, Gli3, Hes1 and Hes5, and stimulated the formation of proliferating MGPCs in damaged retinas. In undamaged retinas, SAG or rhShh had no apparent effect upon the Müller glia. However, SAG combined with FGF2 potentiated the formation of MGPCs, whereas SAG combined with IGF1 stimulated the nuclear migration of Müller glia, but not the formation of MGPCs. Conversely, inhibition of Hh signaling with KAAD-cyclopamine, Gli antagonists or antibody to Shh reduced numbers of proliferating MGPCs in damaged and FGF2-treated retinas. Hh signaling potentiates Pax6, Klf4 and cFos expression in Müller glia during the formation of MGPCs. We find that FGF2/MAPK signaling recruits Hh signaling into the signaling network that drives the formation of proliferating MGPCs. Our findings implicate Hh signaling as a key component of the network of signaling pathways that promote the de-differentiation of Müller glia and proliferation of MGPCs.

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Serotonin released from amacrine neurons is scavenged and degraded in bipolar neurons in the retina

Cited by 56 publications

References 40 publications

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

mTor-signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina

Hedgehog-signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the retina

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