Glucocorticoid receptors in the retina, Muller glia and the formation of Muller glia-derived progenitors
Glucocorticoid receptors in the retina, Muller glia and the formation of Muller glia-derived progenitors
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DOI：
10.1242/dev.109835
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发表时间：
2014-09-01
期刊：
影响因子：
4.6
通讯作者：
Fischer, Andy J.
中科院分区：
文献类型：
--
作者：
Gallina, Donika;Zelinka, Christopher;Fischer, Andy J.
识别影响Muller胶质细胞重新编程为神经源性视网膜前体细胞的信号通路是利用这些细胞再生视网膜的潜力的关键。糖皮质激素受体(GCR)信号通常与抗炎反应有关，GCR激动剂被广泛用于治疗眼部炎症性疾病，尽管视网膜中的细胞靶点和作用机制尚不清楚。我们发现，通过GCR的信号对Muller神经胶质细胞成为增殖MGPC的能力有显著影响。GCR在视网膜中的主要氨基酸序列和表达模式在包括鸡、小鼠、豚鼠、狗和人类在内的脊椎动物物种中高度保守。在所有这些物种中，我们发现GCR由Muller神经胶质细胞表达。在雏鸡视网膜中，我们发现GCR由周边区的前体细胞表达，在急性损伤的视网膜中由Muller胶质细胞上调。GCR信号的激活抑制了MGPC的形成，并拮抗了Muller胶质细胞中FGF2/MAPK信号。相反，我们发现抑制GCR信号刺激了受损视网膜中增殖的MGPC的形成，并在促进神经元分化的同时减少了神经胶质细胞的分化。鉴于GCR在不同脊椎动物视网膜中的保守表达模式，我们认为GCR信号的功能和机制是高度保守的，并通过Muller神经胶质细胞介导。我们得出结论，GCR信号直接抑制MGPC的形成，至少部分是通过干扰FGF2/MAPK信号。
Identification of the signaling pathways that influence the reprogramming of Muller 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 Muller glia to become proliferating Muller 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 Muller glia. In the chick retina, we find that GCR is expressed by progenitors in the circumferential marginal zone (CMZ) and is upregulated by Muller glia in acutely damaged retinas. Activation of GCR signaling inhibits the formation of MGPCs and antagonizes FGF2/MAPK signaling in the Muller 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 Muller glia. We conclude that GCR signaling directly inhibits the formation of MGPCs, at least in part, by interfering with FGF2/MAPK signaling.