ASCL1 reprograms mouse Muller glia into neurogenic retinal progenitors
ASCL1 reprograms mouse Muller glia into neurogenic retinal progenitors
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DOI：
10.1242/dev.091355
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发表时间：
2013-06-15
期刊：
影响因子：
4.6
通讯作者：
Reh, Thomas A.
中科院分区：
文献类型：
--
作者：
Pollak, Julia;Wilken, Matthew S.;Reh, Thomas A.
非哺乳动物脊椎动物有很强的能力从穆勒胶质(MG)再生受损的视网膜神经元，MG激活编码神经因子Achaete-scute同源物1(Ascl1；在哺乳动物中也称为Mash1)的基因，并去分化为祖细胞。相比之下，哺乳动物MG的再生反应有限，在损伤后不能上调Ascl1。为了测试ASCL1是否能够恢复哺乳动物MG的神经发生潜能，我们在分离的小鼠MG培养物和完整的视网膜外植体中过表达了ASCL1。感染ASCL1的MG上调了视网膜祖细胞特异性基因，下调了胶质细胞基因。此外，ASCL1将其靶标的染色质从抑制性构型重塑为活性构型。MG来源的祖细胞分化为具有神经元形态的细胞，表达视网膜亚型特异性神经元标记物，并显示神经元样的生理反应。这些结果表明，单个转录因子ASCL1可以诱导成熟MG处于神经源性状态。
Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Muller glia (MG) that activate the gene encoding the proneural factor Achaete-scute homolog 1 (Ascl1; also known as Mash1 in mammals) and de-differentiate into progenitor cells. By contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether ASCL1 could restore neurogenic potential to mammalian MG, we overexpressed ASCL1 in dissociated mouse MG cultures and intact retinal explants. ASCL1-infected MG upregulated retinal progenitor-specific genes and downregulated glial genes. Furthermore, ASCL1 remodeled the chromatin at its targets from a repressive to an active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers and displayed neuron-like physiological responses. These results indicate that a single transcription factor, ASCL1, can induce a neurogenic state in mature MG.