Injury-dependent Müller glia and ganglion cell reprogramming during tissue regeneration requires Apobec2a and Apobec2b.
Injury-dependent Müller glia and ganglion cell reprogramming during tissue regeneration requires Apobec2a and Apobec2b.
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DOI：
10.1523/jneurosci.5603-11.2012
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发表时间：
2012-01-18
期刊：
影响因子：
--
通讯作者：
Goldman D
中科院分区：
文献类型：
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作者：
Powell C;Elsaeidi F;Goldman D
与哺乳动物不同，成年斑马鱼能够再生多种组织，包括CNS组织。在斑马鱼视网膜中，损伤刺激Müller神经胶质去分化成能够再生所有丢失细胞类型的多能视网膜祖细胞。这种去分化是由基因表达程序的重新激活驱动的，这些基因表达程序与早期发育过程中的基因表达程序具有许多共同特征。虽然这些程序重新激活的机制仍然未知，但DNA甲基化的变化可能起着重要作用。为了开始研究DNA去甲基化是否可能有助于视网膜再生，我们表征了未损伤和损伤视网膜中与DNA去甲基化相关的基因的表达。我们发现，两个胞苷脱氨酶（apobec2a和apobec2b）表达的基础上未受伤的视网膜，他们被诱导增殖，去分化的Müller胶质细胞。apobec2b的最大诱导需要Ascl1a，但不依赖于Lin28，因此定义了一个独立的信号通路源于Ascl1a。引人注目的是，当Apobec 2a或Apobec 2b被反义吗啉代寡核苷酸敲低时，损伤后Müller胶质细胞的增殖反应显著降低，并且ascl1a及其靶基因的损伤依赖性诱导被抑制，这表明Apobec蛋白和ascl1a之间存在调节反馈环。最后，发现Ascl1a、Apobec2a和Apobec2b对于视神经再生是必需的。这些数据确定了Apobec蛋白在视网膜和视神经再生过程中的重要作用，并表明DNA去甲基化可能是细胞重编程以产生再生反应的基础。
Unlike mammals, adult zebrafish are able to regenerate multiple tissues including those of the CNS. In the zebrafish retina, injury stimulates Müller glia dedifferentiation into a multipotent retinal progenitor that is capable of regenerating all lost cell types. This dedifferentiation is driven by the reactivation of gene expression programs that share many characteristics with those that operate during early development. Although the mechanisms underlying the reactivation of these programs remain unknown, it is likely that changes in DNA methylation play a significant role. To begin investigating whether DNA demethylation may contribute to retina regeneration, we characterized the expression of genes associated with DNA demethylation in the uninjured and injured retina. We found that two cytidine deaminases (apobec2a and apobec2b) were expressed basally in the uninjured retina and that they were induced in proliferating, dedifferentiated Müller glia. The maximal induction of apobec2b required Ascl1a, but was independent of Lin28, and therefore defines an independent signaling pathway stemming from Ascl1a. Strikingly, when Apobec2a or Apobec2b was knocked down by antisense morpholino oligonucleotides, the proliferative response of Müller glia following injury was significantly reduced and injury-dependent induction of ascl1a and its target genes were inhibited, suggesting the presence of a regulatory feedback loop between Apobec proteins and ascl1a. Finally, Ascl1a, Apobec2a and Apobec2b were found to be essential for optic nerve regeneration. These data identify an essential role for Apobec proteins during retina and optic nerve regeneration and suggest DNA demethylation may underlie the reprogramming of cells to mount a regenerative response.