The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development

Abstract

MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA‐generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain‐derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca2+‐dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre‐miR16, was impaired. Decreased production of miR‐16‐5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane‐targeted TRBP. Moreover, miR‐16‐5p or membrane‐targeted TRBP expression blocked BDNF‐induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity‐dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function.

Neural maturation enhanced by exercise-induced extracellular derivatives

“…miR16, -342, -7a, -674, -101, etc. are known to affect neuronal function and have been reported to be involved in energy metabolism [49][50][51][52][53][54][55][56] . miRNAs are known to regulate not only target genes but also their pathways.…”

When TRBP leaves Dicer at the alt‐’ER

“…In conclusion, the work by Antoniou et al reports a novel mechanism of BDNF‐induced regulation of pre‐miRNA processing, via the dynamic association of TRBP and Dicer at the ER membranes. Therefore, compartmentalization is created via utilization of locally distributed organelles, the ER, for regulation of RNA metabolism.…”

“…In the new work, Antoniou et al characterize a related mechanism for local miRNA biogenesis, by demonstrating that BDNF‐induced neuritogenesis depends on the dynamic redistribution of TRBP away from the ER. When TRBP redistributes from the ER to the cytoplasm, it dissociates from Dicer, thus reducing dicing activity and miR‐16 production.…”

“…Is the BDNF‐dependent TRBP switch one of several means for modifying miRNA profiles? For example, BDNF‐induced global dicing enhancement, concomitant with specific destabilization of Let‐7 miRNAs , suggests that other mechanisms are probably awaiting discovery. miR‐16 represses the mRNA encoding for BDNF, a secretory protein that is translated at the neuron rough ER, and BDNF regulates miR‐16 levels . What are the properties and kinetics of the proposed miR‐16‐BDNF feedback loop?…”

“…However, research shows that there are many degrees of complexity to miRNA regulation. A new study by Antoniou et al that is published in this issue of EMBO Reports explores an interesting neuron‐specific facet of miRNA biogenesis. We learn that in neuronal dendrites, the endoplasmic reticulum (ER) acts as a regulatory domain for the dynamic encounter of TRBP and Dicer, two proteins required for the biogenesis of miRNAs, thus affecting neuron morphogenesis.…”