Abstract
Neural progenitor cells (NPCs) derived from human embryonic stem cells (hESCs) have great potential in cell therapy, drug screening and toxicity testing of neural degenerative diseases. However, the molecular regulation of their proliferation and apoptosis, which needs to be revealed before clinical application, is largely unknown. MicroRNA miR-195 is known to be expressed in the brain and is involved in a variety of proapoptosis or antiapoptosis processes in cancer cells. Here, we defined the proapoptotic role of miR-195 in NPCs derived from two independent hESC lines (human embryonic stem cell-derived neural progenitor cells, hESC-NPCs). Overexpression of miR-195 in hESC-NPCs induced extensive apoptotic cell death. Consistently, global transcriptional microarray analyses indicated that miR-195 primarily regulated genes associated with apoptosis in hESC-NPCs. Mechanistically, a small GTP-binding protein ADP-ribosylation factor-like protein 2 (ARL2) was identified as a direct target of miR-195. Silencing ARL2 in hESC-NPCs provoked an apoptotic phenotype resembling that of miR-195 overexpression, revealing for the first time an essential role of ARL2 for the survival of human NPCs. Moreover, forced expression of ALR2 could abolish the cell number reduction caused by miR-195 overexpression. Interestingly, we found that paraquat, a neurotoxin, not only induced apoptosis but also increased miR-195 and reduced ARL2 expression in hESC-NPCs, indicating the possible involvement of miR-195 and ARL2 in neurotoxin-induced NPC apoptosis. Notably, inhibition of miR-195 family members could block neurotoxin-induced NPC apoptosis. Collectively, miR-195 regulates cell apoptosis in a context-dependent manner through directly targeting ARL2. The finding of the critical role of ARL2 for the survival of human NPCs and association of miR-195 and ARL2 with neurotoxin-induced apoptosis have important implications for understanding molecular mechanisms that control NPC survival and would facilitate our manipulation of the neurological pathogenesis.
Highlights
During the past decade, a new class of regulatory genes known as microRNAs has attracted a great deal of attention as an additional layer of mRNA regulation in eukaryotes
We demonstrated the role of miR-195 in coordinating neural progenitor cell (NPC) survival and apoptosis at the early stage of neural differentiation and identified a GTP-binding protein, ADP-ribosylation factor-like protein 2 (ARL2), as a genuine functional target of miR-195 in these biological processes
As it has been reported that miR-195 affected cell cycle or cell apoptosis in other cell types,[12,15] we examined whether the NPC cell number reduction after overexpression of miR-195 was due to cell cycle alteration or increased cell apoptosis
Summary
A new class of regulatory genes known as microRNAs (miRNAs) has attracted a great deal of attention as an additional layer of mRNA regulation in eukaryotes. Received 10.7.12; revised 22.3.13; accepted 29.4.13; Edited by P Salomoni miR-195 induces apoptosis in hESC-derived NPCs Y Zhou et al miRNAs negatively regulate target gene expression through mRNA translation repression or degradation.[5] The human genome is predicted to contain over 1000 miRNAs, about 3% of the total number of human genes.[5] They are known to have important roles in diverse biological processes, including cancer pathogenesis,[6] neural development,[7] cell cycle regulation[8] and so on. A feature of miRNAs is that they can modulate the expression of many genes simultaneously, making them powerful post-transcriptional regulators.[9] a single miRNA could execute different biological functions in different cell types. Despite all these progresses in miR-195 research, the functions of miR-195 in human NPCs have not been examined
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