miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a

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.

MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

“…MicroRNAs regulate dendrite branching out via AKT pathway, which is known to play roles in the regulation of dendritic morphogenesis and to increase the complexity of the dendritic tree (Kumar et al, 2005; Xue et al, 2016). We found that overexpression of miR-182 increased the activity of AKT in T308 and S473 and blockage of the endogenous miR-182 inhibited AKT activity ( Figures 5A,B ), but there are no effects on Erk activity by miR-182 ( Supplementary Figure S3 ).…”

“…The PTEN/AKT pathway regulated by microRNAs plays important roles in neuronal maturation. MiR-9 and miR-124 regulate dendritic branching via AKT/GSK3β pathway (Xue et al, 2016); PTEN/miR-29a pathway modulates neurite outgrowth (Zou et al, 2015). In neuronal regeneration, PTEN/AKT pathway regulated by microRNA bantam enhances the regeneration of sensory neuron axons and dendrites (Song et al, 2012).…”

Deep sequencing of small RNAs from 11 tissues of grass carp Ctenopharyngodon idella and discovery of sex‐related microRNAs

“…Thus, research on tissue‐differential miRNAs could reveal mechanisms of functional gene regulation in multiple tissues. A review of the existing literature revealed that in the most heterogeneous brain tissue of C. idella in which miRNAs are most highly expressed, miR‐9, miR‐124, miR‐134 and miR‐153 have an important biological function in neural development and maturation (Schratt et al ., ; Tsai et al ., ; Xue et al ., ), while miR‐132 and miR‐let7i exert anti‐inflammatory effects in the brain (Jickling et al ., ; O'Neill, ). GO enrichment analysis revealed that targets of brain‐enriched miRNAs are linked to biological processes associated with normal brain function (Figure (a)).…”

Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System

“…Many of these miRNAs also exhibited overlapping cellular functions, contributing to processes such as tumorigenesis [23][24][25][26][27][28][29][30], differentiation [31][32][33], proliferation [34][35][36][37][38], apoptosis [39][40][41][42], and cell cycle regulation [34,43,44]. A subset of the miRNAs was associated with nervous system-specific processes, such as differentiation [45][46][47][48][49], lifespan [50], neurite guidance [51][52][53], or synaptogenesis [54][55][56]. We were specifically interested in miRNAs known to contribute to neuronal differentiation and/or axonal guidance, processes that are known to be regulated by RA [10,57].…”