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

Abstract

M€ uller 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 M€ uller 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 M€ uller glia in the chicken retina. In response to acute retinal damage, we found that M€ uller 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 M€ uller 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 FGFreceptors 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 M€ uller glia into progenitor-like cells. V V C

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

“…Therefore, it is possible that suppressed formation of MGPCs in CpdA/NMDA-or Dex/NMDA-treated retinas resulted, at least in part, secondarily through diminished microglial reactivity and/or diminished levels of neuronal damage. Nevertheless, we propose that GCR signaling primarily inhibits the formation of MGPCs by directly influencing the Müller glia for the following reasons: (1) GCR is expressed by Müller glia, not by retinal microglia or neurons; (2) FGF/MAPK signaling is known to directly stimulate Müller glia (Fischer et al, 2009b) and activation of GCR signaling blocks FGF2-mediated formation of MGPCs in damaged retinas (current study); and (3) in the absence of retinal damage, activation of GCR signaling inhibits the formation of MGPCs in response to FGF2. In addition to the inhibition of MAPK signaling, activation of GCR inhibited FGF2-mediated accumulation of pS6, a readout of mTor signaling.…”

“…Tissues were fixed, sectioned and immunolabeled as described previously (Fischer et al, 2008(Fischer et al, , 2009b. Working dilutions and sources of primary and secondary antibodies used in this study are listed in supplementary material Table S2.…”

ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination

“…Deletion of Pten, a negative regulator of PI3K-AKT signaling, results in cerebellar lamination deficits (Marino et al, 2002;Yue et al, 2005), suggesting that normal levels of PI3K-AKT activity are important for cerebellar lamination. GRB2, an adaptor protein, can bind to two phosphorylated tyrosine residues in the ICD of ERBB3 and activate the MAPK signaling cascade, which has been implicated in proliferation of glial cells (Fischer et al, 2009;Schulze et al, 2005;Zhang and Liu, 2002). Moreover, the adaptor CRK has high affinity for pY1276 in the ICD of ERBB3.…”

A GtPase Rac1 participa da proliferação de células gliais de Müller após lesão excitotóxica.

“…A retina de peixes apresenta uma admirável regeneração proveniente das células gliais de Müller (Bernardos et al, 2007 (Fischer et al, 2009a, Fischer et al, 2009b. Contudo, a ativação apenas desta via não é suficiente para induzir a entrada de células de Müller novamente no ciclo celular, visto que a via de Notch parece atuar em conjunto com a via de MAPK (Ghai et al 2010).…”

“…Neste sentido, destaca-se o FGF (fator de crescimento de fibroblasto), um fator de crescimento liberado após lesão que estimula a proliferação de células gliais de Müller de coelho (Lewis et al, 1992), aves (Fischer e Reh, 2002) e linhagens humanas (Hollborn et al, 2004). Em aves, o FGF ativa a via MAPK e esta ativação deve ser sustentada para que ocorra a proliferação de células gliais de Müller (Fischer et al, 2009b). Essa via de FGF/MAPK depende da via Notch (Ghai et al, 2010), que tem função temporal específica.…”