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A Reporter Assay to Analyze Intronic microRNA Maturation in Mammalian Cells
Published on: June 16, 2022
A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic
Gabriele Siegel1, Gregor Obernosterer, Roberto Fiore
1Interdisziplinäres Zentrum für Neurowissenschaften, SFB488 Junior Group, Universität Heidelberg, and Institut für Neuroanatomie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
Abstract:
The microRNA pathway has been implicated in the regulation of synaptic protein synthesis and ultimately in dendritic spine morphogenesis, a phenomenon associated with long-lasting forms of memory. However, the particular microRNAs (miRNAs) involved are largely unknown. Here we identify specific miRNAs that function at synapses to control dendritic spine structure by performing a functional screen. One of the identified miRNAs, miR-138, is highly enriched in the brain, localized within dendrites and negatively regulates the size of dendritic spines in rat hippocampal neurons. miR-138 controls the expression of acyl protein thioesterase 1 (APT1), an enzyme regulating the palmitoylation status of proteins that are known to function at the synapse, including the alpha(13) subunits of G proteins (Galpha(13)). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized Galpha(13) both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of Galpha(13) might be an important downstream event of miR-138 function. Our results uncover a previously unknown miRNA-dependent mechanism in neurons and demonstrate a previously unrecognized complexity of miRNA-dependent control of dendritic spine morphogenesis.
Insights
Researchers identified microRNAs (miRNAs) controlling dendritic spine structure. Specifically, miR-138 regulates acyl protein thioesterase 1 (APT1) to control synaptic plasticity and memory formation.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The microRNA pathway regulates synaptic protein synthesis and dendritic spine morphogenesis, crucial for long-lasting memory.
- Specific microRNAs (miRNAs) involved in synaptic regulation remain largely unidentified.
Purpose of the Study:
- To identify specific miRNAs that regulate dendritic spine structure at synapses.
- To elucidate the molecular mechanisms by which identified miRNAs control neuronal morphology.
Main Methods:
- Functional screening to identify miRNAs impacting dendritic spine structure.
- In situ hybridization to determine miRNA localization in neurons.
- RNA-interference (RNAi) mediated knockdown to assess gene function.
- Analysis of protein palmitoylation status.
Main Results:
- miR-138 was identified as a key miRNA enriched in the brain and localized in dendrites.
- miR-138 negatively regulates dendritic spine size in rat hippocampal neurons.
- miR-138 controls the expression of acyl protein thioesterase 1 (APT1), affecting synaptic protein palmitoylation.
- APT1 regulates the palmitoylation of G protein alpha(13) subunits (Galpha(13)), impacting spine morphology.
Conclusions:
- A novel miRNA-dependent mechanism controlling dendritic spine morphogenesis in neurons was uncovered.
- miR-138 and its downstream targets, APT1 and Galpha(13), play a critical role in regulating synaptic structure and plasticity.
- This study reveals previously unrecognized complexity in miRNA-mediated control of neuronal structure relevant to memory.
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