Pten inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated Dynlt1a and Lars2.
Pten inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated Dynlt1a and Lars2.
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Pten 抑制使长距离轴突再生的本质光敏视网膜神经节细胞去分化，并上调线粒体相关的 Dynlt1a 和 Lars2。
DOI：
10.1242/dev.201644
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发表时间：
2023-04-15
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影响因子：
--
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中枢神经系统投射神经元不能自发再生受损的轴突。靶向发育调节基因以重新激活胚胎内在轴突生长能力或靶向促生长肿瘤抑制基因如Pten仅在一小部分受损的视网膜神经节细胞（RGC）中促进长距离轴突再生，尽管许多RGC再生短距离轴突。最近的一项研究确定α RGC是响应Pten抑制而再生短距离轴突的主要类型，但再生长距离轴突的罕见类型以及实现这种响应的细胞特征仍然未知。在这里，我们使用了一种新的方法来专门捕获罕见的长距离轴突再生RGC，并将其转录组与胚胎RGC进行比较，以回答这些问题。我们发现存在保留胚胎细胞状态特征的成人非α内在光敏M1 RGC亚型，并表明这些亚型部分向胚胎状态去分化，并响应Pten抑制再生长距离轴突。我们还鉴定了Pten抑制上调的神经元相关基因Dynlt1a和Lars2，它们自身促进轴突再生，因此提出了新的治疗靶点。总结：一种用于捕获长距离轴突再生RGC进行单细胞RNA测序分析的新方法揭示了保留胚胎细胞状态特征的成人神经元亚型对治疗的反应是去分化。
Central nervous system projection neurons fail to spontaneously regenerate injured axons. Targeting developmentally regulated genes in order to reactivate embryonic intrinsic axon growth capacity or targeting pro-growth tumor suppressor genes such as Pten promotes long-distance axon regeneration in only a small subset of injured retinal ganglion cells (RGCs), despite many RGCs regenerating short-distance axons. A recent study identified αRGCs as the primary type that regenerates short-distance axons in response to Pten inhibition, but the rare types which regenerate long-distance axons, and cellular features that enable such response, remained unknown. Here, we used a new method for capturing specifically the rare long-distance axon-regenerating RGCs, and also compared their transcriptomes with embryonic RGCs, in order to answer these questions. We found the existence of adult non-α intrinsically photosensitive M1 RGC subtypes that retained features of embryonic cell state, and showed that these subtypes partially dedifferentiated towards an embryonic state and regenerated long-distance axons in response to Pten inhibition. We also identified Pten inhibition-upregulated mitochondria-associated genes, Dynlt1a and Lars2, which promote axon regeneration on their own, and thus present novel therapeutic targets. Summary: A new method for capturing long-distance axon-regenerating RGCs for single-cell RNA-sequencing analysis reveals that adult neuronal subtypes that retain features of the embryonic cell state dedifferentiate in response to a treatment.
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影响因子：
64.8
作者：
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DOI：
10.1073/pnas.1119449109
发表时间：
2012-06-05
影响因子：
11.1
作者：
de Lima, Silmara;Koriyama, Yoshiki;Benowitz, Larry
通讯作者：
Benowitz, Larry