Abstract
BackgroundThe Notch signaling pathway regulates adult neurogenesis under physiological and pathophysiological conditions. MicroRNAs are small non-coding RNA molecules that regulate gene expression. The present study investigated the effect of miR-124a on the Notch signaling pathway in stroke-induced neurogenesis.Methodology and Principal FindingsWe found that adult rats subjected to focal cerebral ischemia exhibited substantial reduction of miR-124a expression, a neuron specific miRNA, in the neural progenitor cells of the subventricular zone (SVZ) of the lateral ventricle, which was inversely associated with activation of Notch signals. In vitro, transfection of neural progenitor cells harvested from the SVZ of adult rat with miR-124a repressed Jagged-1 (JAG1), a ligand of Notch, in a luciferase construct containing the JAG1 target site. Introduction of miR-124a in neural progenitor cells significantly reduced JAG1 transcript and protein levels, leading to inactivation of Notch signals. Transfection of neural progenitor cells with miR-124a significantly reduced progenitor cell proliferation and promoted neuronal differentiation measured by an increase in the number of Doublecortin positive cells, a marker of neuroblasts. Furthermore, introduction of miR-124a significantly increased p27Kip1 mRNA and protein levels, a downstream target gene of the Notch signaling pathway.ConclusionsCollectively, our study demonstrated that in vivo, stroke alters miRNA expression in SVZ neural progenitor cells and that in vitro, miR-124a mediates stroke-induced neurogenesis by targeting the JAG-Notch signaling pathway.
Highlights
The Notch pathway is a highly conserved regulatory signaling network [1] and has been linked to a variety of pathogenic conditions in human [2]
We and others have demonstrated that focal cerebral ischemia activates the Notch signaling pathway in neural progenitor cells localized to the subventricular zone (SVZ) of the lateral ventricle, leading to expansion of neural progenitor cells [3], [4], [5], [6]
To examine the expression profile of miRNAs after focal cerebral ischemia, we analyzed the global expression of mature miRNAs in cultured neural progenitor cells isolated from the SVZ in rats 7 days after right middle cerebral artery occlusion (MCAo, n = 3 individual cultured SVZ cells, Table S1)
Summary
The Notch pathway is a highly conserved regulatory signaling network [1] and has been linked to a variety of pathogenic conditions in human [2]. Mature miRNA molecules are either fully or partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to down-regulate gene expression [7]. MiRNAs have been recently shown to be crucial in regulating a variety of pathophysiological processes, including immune function, tumorigenesis, metabolism, and cell proliferation [8], [9], [10]. MiR-124, a preferentially expressed miRNA in neurons, has recently been implicated in the positive modulation of the transitory progression of adult SVZ neurogenesis by repressing Sox9 [14], indicating that this specific miRNA is critical for the homeostasis of differentiation versus proliferation of adult neural progenitor cells [14], [15]. The Notch signaling pathway regulates adult neurogenesis under physiological and pathophysiological conditions. MicroRNAs are small non-coding RNA molecules that regulate gene expression. The present study investigated the effect of miR-124a on the Notch signaling pathway in stroke-induced neurogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
