The Reactivity, Distribution and Abundance of Non-Astrocytic Inner Retinal Glial (NIRG) Cells Are Regulated by Microglia, Acute Damage, and IGF1

Zelinka, Christopher; Scott, Melissa A.; Volkov, Leo; Fischer, Andy J.

doi:10.1371/journal.pone.0044477

Cited by 49 publications

(81 citation statements)

References 55 publications

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“…Microglia play an important role in zebrafish brain regeneration and macrophages impact limb regeneration in salamanders 116,117 . Following retinal injury, microglia become activated and migrate to the injury site 89,90,118 , perhaps suggesting a role in retina regeneration. Further analysis of their contribution to retina regeneration in zebrafish is warranted and if they play an important role, comparing their injury response with that of mammals may suggest strategies for improving mammalian retina regeneration.…”

Section: Future Prospectsmentioning

confidence: 99%

Müller glial cell reprogramming and retina regeneration

2014

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Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development and they function to maintain retinal homeostasis and integrity. In mammals, Müller glia respond to retinal injury in a variety of ways that can be either protective or detrimental to retinal function. Although under special circumstances these cells can be coaxed to proliferate and generate neurons, these responses are meager and insufficient for repairing a damaged retina. By contrast, in teleost fish (such as zebrafish) the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and allows them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision. Recent studies have revealed a number of important mechanisms underlying Müller glia reprogramming and retina regeneration in fish that may lead to new strategies for stimulating retina regeneration in mammals.

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Section: Future Prospectsmentioning

confidence: 99%

Müller glial cell reprogramming and retina regeneration

2014

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“…Quantitative PCR cDNA was synthesized as described using standard protocols and qRT-PCR performed as described previously (Fischer et al, 2004Zelinka et al, 2012). PCR primers were designed using the Primer-BLAST design tool at NCBI (http://www.ncbi.nlm.nih.gov/tools/primer-blast/).…”

Section: Labeling For Edumentioning

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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“…Central retina was defined as the region within a 3 mm radius of the posterior pole of the eye, and peripheral retina was defined as an annular region between 3 mm and 0.5 mm from the CMZ. The identity of BrdU-labeled cells was determined based on previous findings that all proliferating cells in the chick retina are Sox2/9 + Müller glia in the INL/ONL, Sox2/9/Nkx2.2 + NIRG cells in the IPL, GCL and NFL (the NIRG cells do not migrate distally into the retina), and CD45 + (Sox2/ 9 − ) microglia Zelinka et al, 2012). Sox2 + nuclei in the INL were identified as Müller glia based on their large size and fusiform shape, which was distinctly different from the Sox2 + nuclei of cholinergic amacrine cells, which are small and round .…”

Section: Photography Cell Counts and Statisticsmentioning

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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The Reactivity, Distribution and Abundance of Non-Astrocytic Inner Retinal Glial (NIRG) Cells Are Regulated by Microglia, Acute Damage, and IGF1

Cited by 49 publications

References 55 publications

Müller glial cell reprogramming and retina regeneration

Müller glial cell reprogramming and retina regeneration

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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