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Utilizing Combined Methodologies to Define the Role of Plasma Membrane Delivery During Axon Branching and Neuronal Morphogenesis
Published on: March 16, 2016
The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development
Anna Antoniou1, Sharof Khudayberdiev2, Agata Idziak2
1Institute for Physiological Chemistry, Biochemical-Pharmacological Center Marburg, Philipps-University of Marburg, Marburg, Germany anna.antoniou@staff.uni-marburg.de gerhard.schratt@hest.ethz.ch.
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.
Insights
Neurons regulate microRNA production at intracellular membranes. Brain-derived neurotrophic factor (BDNF) disrupts this process, impacting neuronal development and circuit formation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- MicroRNAs (miRNAs) are crucial regulators of local protein synthesis during neuronal development.
- The miRNA-generating complex, including Dicer, TRBP, and PACT, is key to miRNA biogenesis.
- Neuronal development relies on precise regulation of gene expression in dendrites.
Purpose of the Study:
- To investigate the dynamic regulation of miRNA production in developing neurons.
- To understand the role of intracellular membranes and specific proteins in miRNA biogenesis.
- To elucidate the impact of neurotrophic factors on miRNA processing and neuronal structure.
Main Methods:
- Immunofluorescence and cell fractionation to localize miRNA-generating complex components.
- Biochemical assays to assess protein-protein interactions and miRNA processing.
- Calcium imaging and manipulation to study signaling pathways.
- Genetic manipulation (e.g., expression of specific protein variants) to rescue or block miRNA production and cellular processes.
Main Results:
- The miRNA-generating complex predominantly associates with intracellular membranes in developing neurons.
- Brain-derived neurotrophic factor (BDNF) stimulation induces calcium-dependent TRBP redistribution and dissociation from Dicer.
- This dissociation impairs the processing of specific neuronal miRNAs, including pre-miR16, affecting miR-16-5p production.
- Restoring membrane localization of TRBP or expressing miR-16-5p inhibited BDNF-induced dendrite growth.
Conclusions:
- Neuronal TRBP dynamics at intracellular membranes are critical for activity-dependent neuronal development.
- Neurons utilize specialized mechanisms involving dynamic regulation of miRNA biogenesis factors at the endoplasmic reticulum.
- This regulation is essential for controlling dendrite complexity, neuronal circuit formation, and overall brain function.
