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Mitogen-activated protein kinase-signaling stimulates Muller glia to proliferate in acutely damaged chicken retina.

ABSTRACT: Müller glia in the mature retina have the capacity to become progenitor-like cells in a many different vertebrate classes. The cell-signaling pathways that control the ability of mature Müller glia to become progenitor-like cells remain uncertain. The purpose of this study was to investigate the roles of the Mitogen-Activated Protein Kinase (MAPK) pathway in regulating the activity of Müller glia in the chicken retina. In response to acute retinal damage, we found that Müller glia accumulated phosphorylated ERK1/2 and phospho-CyclicAMP Response Element Binding-protein (pCREB), and transiently expressed immediate early genes, cFos and Egr1, that are known to be downstream of MAPK-signaling. Egr1 and pCREB were normally expressed by retinal progenitors in the circumferential marginal zone (CMZ), whereas cFos and pERK1/2 were not. In addition, small molecule inhibitors of MEK (UO126) and the FGF-receptor (SU5402) suppressed the proliferation of Müller glia-derived progenitor-like cells. These inhibitors suppressed the accumulation of Egr1 and pCREB, whereas levels of cFos were unaffected in the glial cells. These findings suggest that Egr1 and pCREB are downstream of the signaling cascade activated by FGF-receptors and ERK1/2. Further, our findings suggest that Egr1 and pCREB may promote glial proliferation. We propose that activation of both the FGF-receptor and ERK1/2-pathway is required for the proliferation and transdifferentiation of Müller glia into progenitor-like cells.

SUBMITTER: Fischer AJ

PROVIDER: S-EPMC2774719 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina.

Fischer Andy J AJ Scott Melissa A MA Tuten William W

Glia 20090101 2

Müller glia in the mature retina have the capacity to become progenitor-like cells in a many different vertebrate classes. The cell-signaling pathways that control the ability of mature Müller glia to become progenitor-like cells remain uncertain. The purpose of this study was to investigate the roles of the Mitogen-Activated Protein Kinase (MAPK) pathway in regulating the activity of Müller glia in the chicken retina. In response to acute retinal damage, we found that Müller glia accumulated ph ...[more]

PMID: 18709648

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Project description:The damaged zebrafish retina replaces lost neurons through a regenerative response that initiates with the asymmetric cell division of Müller glia to produce neuronal progenitor cells that proliferate and migrate to the damaged retinal layer, where they differentiate into the lost neuronal cell types. Because Müller glia are known to phagocytose apoptotic retinal cells during development, we tested if Müller glia engulfed apoptotic rod cell bodies in light-damaged retinas. After 24h of constant intense light, damaged retinas revealed both a strong nuclear TUNEL signal in photoreceptors and a weak cytoplasmic TUNEL signal in Müller glia, although Müller glial apoptosis is not observed in the light-damaged retina. Light damage of a rod-specific transgenic reporter line, Tg(XlRho:EGFP)(fl1), resulted in some Müller glia containing both TUNEL signal and EGFP, which indicated that this subset of Müller glia engulfed apoptotic photoreceptor cell bodies. To determine if phagocytosis induced the Müller glial proliferative response in the light-damaged retina, we utilized O-phospho-l-serine (L-SOP), a molecule that mimics the phosphatidylserine head group and partially blocks microglial phagocytosis of apoptotic cells. Intravitreal injection of L-SOP immediately prior to beginning constant intense light treatment: i) did not significantly reduce light-induced photoreceptor cell death, ii) significantly reduced the number of PCNA-positive Müller glia, and iii) significantly reduced the number of cone photoreceptors in the regenerated retina relative to control retinas. Because L-SOP is also a specific group III metabotropic glutamate receptor (mGluR) agonist, we also tested if the more potent specific group III agonist, L-2-amino-4-phosphonobutyrate (L-AP4), the specific group III antagonist (RS)-α-Methylserine-O-phosphate (MSOP) or the specific group I antagonist, L-2-amino-3-phophonopropanoic acid (L-AP3) affected Müller glial proliferation. We found no changes with any of these factors compared to control retinas, revealing that metabotropic glutamate receptors were not necessary in the Müller glia proliferative response. Furthermore, ascl1a and stat3 expression were unaffected in either the L-SOP or MSOP-injected retinas relative to controls, suggesting L-SOP disrupts Müller glia proliferation subsequent to or in parallel with ascl1a and stat3 activation. This implies that at least one signaling mechanism, in addition to the process disrupted by L-SOP, is required to activate Müller glia proliferation in the light-damaged retina.

Dataset Information

Mitogen-activated protein kinase-signaling stimulates Muller glia to proliferate in acutely damaged chicken retina.

Publications

Mitogen-activated protein kinase-signaling stimulates Müller glia to proliferate in acutely damaged chicken retina.

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