MicroRNA‐mediated non‐cell‐autonomous regulation of cortical radial glial transformation revealed by a Dicer1 knockout mouse model
MicroRNA‐mediated non‐cell‐autonomous regulation of cortical radial glial transformation revealed by a Dicer1 knockout mouse model
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DOI：
10.1002/glia.22789
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发表时间：
2015-05
期刊：
影响因子：
6.2
通讯作者：
Chi Zhang;Xinxu Ge;Qian Liu;Mei Jiang;Matthew W. Li;Hedong Li
中科院分区：
文献类型：
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作者：
Chi Zhang;Xinxu Ge;Qian Liu;Mei Jiang;Matthew W. Li;Hedong Li
径向胶质细胞（RG）作为神经源性祖细胞和神经元迁移支架，在皮层神经发生过程中起着至关重要的作用。RG向星形胶质细胞的转化，标志着这些细胞从发育功能向生理功能的转变，是皮层发育的重要步骤。在这项研究中，我们旨在确定microRNAs （miRNAs）在这一生物学过程中的作用。在RG及其后代中Dicer1缺失的条件小鼠中，我们观察到RG转化延迟，其径向过程持续存在，并且出生后大脑皮层中易位RG细胞体的数量和复杂性降低。Notch1信号的下调对RG转化至关重要，并且我们一致发现Notch1信号在Dicer1缺失的大脑皮层中增强。此外，我们发现，在Notch1配体中，Jagged2 （Jag2）在出生后Dicer1缺失的大脑皮层以及Dicer1缺失的原代胚胎皮层培养物中优先上调。功能上，在RG克隆L2.3中，Dicer1缺失的出生后小脑细胞Jag2表达升高，在共培养时比对照细胞刺激更强的Notch1信号。因此，我们揭示了一种新的非细胞自主机制，该机制通过miRNA介导的Notch1配体Jag2的抑制来调节Notch1信号传导，从而调节RG转化。此外，我们验证了Jag2是miR‐124的靶基因，并在体外证明Jag2的表达对Dicer1缺失高度敏感。最后，我们提出了MiRNA敏感靶基因的新概念，其鉴定可能揭示MiRNA介导的基因表达调控的独特模式。神经胶质2015;63:860 - 876
Radial glia (RG), as neurogenic progenitors and neuronal migration scaffolds, play critical roles during cortical neurogenesis. RG transformation into astrocytes, marking the transition from developmental to physiological function of these cells, is an important step during cortical development. In this study, we aim to determine the roles of microRNAs (miRNAs) during this biological process. In a conditional Dicer1‐null mouse where Dicer1 is deleted in both RG and their neuronal progeny, we observe delayed RG transformation as revealed by the persistence of their radial processes, and reduced number and complexity of translocated RG cell bodies in the postnatal cerebral cortex. Downregulation of Notch1 signaling is crucial to RG transformation, and consistently we find that Notch1 signaling is enhanced in the Dicer1‐null cerebral cortex. In addition, we show that, among the Notch1 ligands, Jagged2 (Jag2) is preferentially upregulated in the postnatal Dicer1‐null cerebral cortex as well as primary embryonic cortical cultures with instant Dicer1 deletion. Functionally, Dicer1‐deleted postnatal cerebellar cells with elevated Jag2 expression stimulate a stronger Notch1 signaling in a RG clone L2.3 when co‐cultured than control cells. Therefore, we unravel a novel non‐cell‐autonomous mechanism that regulates RG transformation by modulating Notch1 signaling via miRNA‐mediated suppression of the Nocth1 ligand Jag2. Furthermore, we validate Jag2 as a miR‐124 target gene and demonstrate in vitro that Jag2 expression is highly sensitive to Dicer1 deletion. Finally, we propose a new concept of MiRNA‐Sensitive target genes, identification of which may unravel a unique mode of miRNA‐mediated gene expression regulation. GLIA 2015;63:860–876