MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

Abstract

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons

“…We have shown that the miR-17-92 cluster within distal axons of cortical neurons locally promotes axonal growth by targeting PTEN/mTOR signals [16]. Others also demonstrate that miR-338[59], miR-132[13], miR-9 [60], miR-8[61] are enriched in distal axons and regulate their target genes involving energy metabolism and cytoskeleton function leading to modulating axonal growth. Distal axons contain miRNA machinery proteins [60,59,16,13].…”

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].…”

Noncoding RNAs and Their Potential Therapeutic Applications in Tissue Engineering

“…miR-21 and miR-222 promote neurite outgrowth by targeting Sprouty2 and PTEN, respectively [40,41]. miR-8, miR-431, miR-145, and miR-138 have been shown to play regulatory roles in neurite outgrowth [42][43][44]46]. In addition, lncRNA-uc.217 regulates neurite outgrowth in DRG neurons following peripheral nerve injury [45].…”

“…Neural stem/progenitor cells Promote proliferation miR-25 [12]; miR-137 [13]; miR-184 [14]; miR-195 [15] Induce differentiation miR-9, siRNA-TLX [16]; let-7d [17]; miR-137 [13]; miR-184 [14]; miR-195 [15]; miR-34a [18]; lncRNA-BDNF-AS, siRNA-BDNF-AS [19] Mesenchymal stem cells Induce differentiation miR-9 [20]; miR-124 [21] Reduce differentiation miR-128 [22] Neuronal cells Inhibit cell death miR-223 [23]; miR-181c [24]; miR-592 [25]; miR-424 [26]; miR-23a-3p [27]; miR-23a/b, miR-27a/b, siRNA-Apaf-1 [28] Promote cell death miR-134 [29]; miR-200c [30]; miR-30a/b [31][32][33]; miR-124 [34]; miR-711 [35] Regulate degeneration and apoptosis miR-20a [36]; miR-29b [37]; miR-146a, siRNA-miR146a [38] Promote neurite outgrowth miR-7 [39]; miR-21 [40]; miR-222, siRNA-PTEN [41]; miR-8 [42]; miR-431 [43]; miR-145 [44]; lncRNA-uc.217 [45]; miR-138, siRNA-SIRT1 [46] Microglial cells Inhibit inflammation let-7c [47]; miR-124, siRNA-C/EBP-α [48] Promote pro-inflammation miR-155 [49] Inhibit activation let-7c-5p [50] Astrocytes P...…”