MiR-34a Represses Numbl in Murine Neural Progenitor Cells and Antagonizes Neuronal Differentiation

被引:51
作者
Fineberg, Sarah K. [1 ,4 ]
Datta, Poppy [2 ]
Stein, Colleen S. [1 ]
Davidson, Beverly L. [1 ,2 ,3 ]
机构
[1] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA
[3] Univ Iowa, Deparment Neurol, Iowa City, IA 52242 USA
[4] Univ Iowa, Med Scientist Training Program, Iowa City, IA 52242 USA
关键词
CENTRAL-NERVOUS-SYSTEM; TUMOR-SUPPRESSOR NETWORK; MICRORNA EXPRESSION; STEM-CELLS; MIRNA EXPRESSION; GENE-EXPRESSION; MOUSE; NOTCH; P53; APOPTOSIS;
D O I
10.1371/journal.pone.0038562
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
MicroRNA (miRNA) function is required for normal animal development, in particular in differentiation pathways from stem cell and precursor populations. In neurogenesis, it is becoming increasingly appreciated that miRNAs act at many stages to ensure proper progression. In this study we examined the role of miR-34a in neural progenitor cells (NPC) derived from murine embryonic cortex. We found that over-expression of miR-34a in NPC significantly reduced the neuron yield upon in vitro induction of differentiation. MiR-34a has several predicted targets in the Notch pathway, which operates to balance progenitor self-renewal and differentiation during cortical neurogenesis. We tested several Notch pathway players for regulation by miR-34a in undifferentiated NPC, and found that mRNA and protein levels of Numbl, a negative regulator of Notch signaling, as well as two downstream pro-neural genes usually blocked by Notch signaling, NeuroD1 and Mash1, were diminished, while Notch1 and Cbf1 transcripts were enhanced by miR-34a over-expression. Using a luciferase reporter assay, we verified the Numbl 3'-UTR as a direct miR-34a target. Correspondingly, knock-down of endogenous miR-34a resulted in increased Numbl, NeuroD1 and Mash1, and reduced Notch1 transcript levels. Together these results implicate Numbl as a physiologically relevant target of miR-34a in NPC, allowing for enhanced Notch signaling and inhibition of neuronal differentiation. This work extends our understanding of miR-34a-mediated control of cell differentiation from cancer to mammalian nervous system development.
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页数:10
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