Fischer Andy J, Scott Melissa A, Tuten William
Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210-1239, USA.
Glia. 2009 Jan 15;57(2):166-81. doi: 10.1002/glia.20743.
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.
在许多不同的脊椎动物类别中，成熟视网膜中的穆勒胶质细胞有能力转变为祖细胞样细胞。控制成熟穆勒胶质细胞转变为祖细胞样细胞能力的细胞信号通路仍不明确。本研究的目的是探究丝裂原活化蛋白激酶（MAPK）通路在调节鸡视网膜中穆勒胶质细胞活性方面的作用。针对急性视网膜损伤，我们发现穆勒胶质细胞积累了磷酸化的ERK1/2和磷酸化环磷酸腺苷反应元件结合蛋白（pCREB），并短暂表达了已知为MAPK信号下游的即刻早期基因cFos和Egr1。Egr1和pCREB通常由圆周边缘区（CMZ）的视网膜祖细胞表达，而cFos和pERK1/2则不然。此外，MEK（UO126）和FGF受体（SU5402）的小分子抑制剂抑制了穆勒胶质细胞衍生的祖细胞样细胞的增殖。这些抑制剂抑制了Egr1和pCREB的积累，而胶质细胞中cFos的水平未受影响。这些发现表明Egr1和pCREB是由FGF受体和ERK1/2激活的信号级联反应的下游。此外，我们的发现表明Egr1和pCREB可能促进胶质细胞增殖。我们提出，FGF受体和ERK1/2通路的激活对于穆勒胶质细胞增殖并转分化为祖细胞样细胞是必需的。
