Abstract
A single microRNA (miRNA) can regulate expression of multiple proteins, and expression of an individual protein may be controlled by numerous miRNAs. This regulatory pattern strongly suggests that synergistic effects of miRNAs play critical roles in regulating biological processes. miR-9 and miR-124, two of the most abundant miRNAs in the mammalian nervous system, have important functions in neuronal development. In this study, we identified the small GTP-binding protein Rap2a as a common target of both miR-9 and miR-124. miR-9 and miR-124 together, but neither miRNA alone, strongly suppressed Rap2a, thereby promoting neuronal differentiation of neural stem cells (NSCs) and dendritic branching of differentiated neurons. Rap2a also diminished the dendritic complexity of mature neurons by decreasing the levels of pAKT and pGSK3β. Our results reveal a novel pathway in which miR-9 and miR-124 synergistically repress expression of Rap2a to sustain homeostatic dendritic complexity during neuronal development and maturation.
Highlights
The total number of dividing cells[21]
Previous studies demonstrated that miR-9 and miR-124 play crucial roles in determining neuron fate. Both of these miRNAs start to be expressed at almost the same time, and their levels gradually increase over the course of neuronal development[22,28,29]
MAP2-positive neurons derived from NSCs co-overexpressing of miR-9 and miR-124 for 7 days had many more dendritic branches than those transfected with control virus or virus expressing miR-9 or miR-124 alone (Fig. 1A). These results suggest that miR-9 and miR-124 can synergistically regulate neurites morphology and promote dendritic branching
Summary
MiR-124 and miR-9 regulate neural lineage differentiation in embryonic stem cells in vitro[22]. MiR-9*and miR-124 reduce proliferation of neural progenitors by repressing the Brg/Brm-associated factor BAF53a, which in turn represses its neuron-specific homolog BAF53b26,27, a critical factor in dendritic development. MiR-9 and miR-124 have some distinct targets, their synergistic effects on neuronal development are still not clear and merit further investigation. We identified Rap2a as a common target gene of miR-9 and miR-124. We found that repression of Rap2a by miR-9 and miR-124 affects the activation of AKT and GSK3β, which control neuronal differentiation and dendritic branching. Our findings reveal a novel pathway that governs dendritic branching via the synergistic effects of miR-9 and miR-124
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