A positive feedback mechanism that regulates expression of miR-9 during neurogenesis.
A positive feedback mechanism that regulates expression of miR-9 during neurogenesis.
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DOI：
10.1371/journal.pone.0094348
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hart RP
中科院分区：
文献类型：
--
作者：
Davila JL;Goff LA;Ricupero CL;Camarillo C;Oni EN;Swerdel MR;Toro-Ramos AJ;Li J;Hart RP
miR-9是一种神经元特异性的miRNA，是神经发生的重要调节因子。在这项研究中，我们确定了miR-9是如何在神经干细胞样细胞的早期分化过程中受到调控的。我们利用两个永生大鼠前体克隆，一个致力于神经发生（L2.2），另一个能够产生神经元和非神经元细胞（L2.3），来可重复地研究早期神经发生。外源性miR-9能够增加L2.3细胞的神经发生。在神经发生过程中，三个能够编码miR-9的基因组位点中只有一个受到调控，该位点的启动子区含有足够的功能元件，以发育调控模式驱动荧光素酶报告基因的表达。此外，在该序列编码的大量潜在调控位点中，Mef 2因其已知的促神经元作用而脱颖而出。在四个Mef 2旁系同源物中，我们发现只有Mef 2C mRNA在神经发生过程中受到调节。去除预测的Mef 2结合位点或敲低Mef 2C表达降低了miR-9-2启动子活性。最后，编码Mef 2C结合配偶体HDAC 4的mRNA显示被miR-9靶向。由于HDAC 4蛋白可以与Mef 2C蛋白或与基因组Mef 2结合序列共免疫沉淀，我们得出结论，miR-9调节至少部分由Mef 2C结合介导，但表达的miR-9具有减少抑制性HDAC 4的能力，以正反馈机制稳定其自身的表达。
MiR-9, a neuron-specific miRNA, is an important regulator of neurogenesis. In this study we identify how miR-9 is regulated during early differentiation from a neural stem-like cell. We utilized two immortalized rat precursor clones, one committed to neurogenesis (L2.2) and another capable of producing both neurons and non-neuronal cells (L2.3), to reproducibly study early neurogenesis. Exogenous miR-9 is capable of increasing neurogenesis from L2.3 cells. Only one of three genomic loci capable of encoding miR-9 was regulated during neurogenesis and the promoter region of this locus contains sufficient functional elements to drive expression of a luciferase reporter in a developmentally regulated pattern. Furthermore, among a large number of potential regulatory sites encoded in this sequence, Mef2 stood out because of its known pro-neuronal role. Of four Mef2 paralogs, we found only Mef2C mRNA was regulated during neurogenesis. Removal of predicted Mef2 binding sites or knockdown of Mef2C expression reduced miR-9-2 promoter activity. Finally, the mRNA encoding the Mef2C binding partner HDAC4 was shown to be targeted by miR-9. Since HDAC4 protein could be co-immunoprecipitated with Mef2C protein or with genomic Mef2 binding sequences, we conclude that miR-9 regulation is mediated, at least in part, by Mef2C binding but that expressed miR-9 has the capacity to reduce inhibitory HDAC4, stabilizing its own expression in a positive feedback mechanism.
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