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The neuronal microRNA system

Key Points

  • microRNAs (miRNAs) are 21 nucleotide transcripts that are predicted to regulate the translation of up to a third of the mRNAs in a cell. The miRNA biogenesis pathway begins with a primary miRNA transcript that is cleaved to an approximately 70 nucleotide precursor. This precursor is transported to the cytoplasm where the mature miRNA is generated by a second cleavage event and subsequently targeted to a specific mRNA in an RNA silencing complex.

  • miRNAs are abundant in the nervous system where they have key roles in development, neural plasticity, and probably a host of other yet-to-be-discovered functions. In development, specific miRNAs have been implicated in patterning, cell specification and axonal pathfinding.

  • A set of miRNAs are turned on during stem cell differentiation when neural precursors become neurons. Among the properties of these miRNAs is the ability to suppress non-neural mRNAs broadly and to shift the fate of precursor cell populations between neurons and glia.

  • Accumulated data have strongly implicated miRNAs in the regulation of apoptosis and indicated that they are likely to contribute to widespread apoptosis that takes place during neural development.

  • Key support for miRNA functions related to neural plasticity include the involvement of miR-134 in targeting LIM-domain kinase 1 in the dendrite to regulate changes in spine size, and the degradation of the helicase, armitage, as a regulator of activity-dependent effects on translation at synapses.

  • Fragile X syndrome is one disease in which miRNA dysfunction is likely to contribute to disease pathology. miRNAs and miRNA-processing proteins are associated with the fragile X mental retardation protein. In addition, many forms of cancer, including glioblastoma, are associated with miRNA dysfunction.

Abstract

A class of small, non-coding transcripts called microRNAs (miRNAs) that provide a crucial and pervasive layer of post-transcriptional gene regulation has recently emerged and become the focus of intense research. miRNAs are abundant in the nervous system, where they have key roles in development and are likely to be important mediators of plasticity. A highly conserved pathway of miRNA biogenesis is closely linked to the transport and translatability of mRNAs in neurons. Although there are nearly 500 known human miRNA sequences, each of only 21 nucleotides, which bind to multiple mRNA targets, the accurate prediction of miRNA targets seems to lie just beyond our grasp. Nevertheless, the identification of such targets promises to provide new insights into many facets of neuronal function.

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Figure 1: microRNA biogenesis pathway.
Figure 2: The 'sensor' technique.
Figure 3: A model for microRNA-mediated effects at the synapse.
Figure 4: microRNA transport to the dendrite.

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Acknowledgements

Thanks to the members of the Kosik lab for insightful discussions and particularly to S. Banerjee and I. Wang for additional comments on the text. Also thanks to M. McManus for comments on the sensor technique.

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DATABASES

OMIM

fragile X syndrome

Tourette's syndrome

FURTHER INFORMATION

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Glossary

Patterning

Establishing, often by diffusion gradients, a distribution of gene expression over a spatial region that defines the region's emerging anatomical organization, and could prefigure tissue differentiation.

Plasticity

Changes that occur in the organization of the brain, either at the macroscopic level with anatomical reorganization, or at the molecular and physiological level, when synapses change their firing thresholds with repetitive stimulation.

Pre-miRNA

The 70–100 nucleotide hairpin RNA processed from the primary microRNA in the nucleus by the double-stranded RNA-specific ribonuclease Drosha.

Pri-miRNA

The initial transcript encoding the microRNA.

Guide strand

The microRNA strand that is incorporated into the RNA-induced silencing complex and forms base pairs with the mRNA strand as a mature microRNA.

Passenger strand

The strand of the microRNA duplex which is removed during the assembly of the RNA-induced silencing complex and which is usually degraded.

Seed region

Positions 2–8 of the 5′ end of the microRNA that are most likely to form an exact match with an mRNA target and are often conserved.

PAZ motif

A conserved nucleic acid-binding structure that is found in members of the DCR and AGO protein families.

PIWI motif

A conserved structure that is found in members of the AGO protein family. It is structurally similar to ribonuclease H domains and, in at least some cases, has endoribonuclease activity.

Slicer

Target RNA cleavage activity in RNA interference, mediated by argonaute 2.

P bodies

Cytoplasmic structures that contain untranslated mRNAs and can serve as sites of mRNA degradation and storage.

Homeotic phenotype

Arises due to mutations in homeotic genes that do not eliminate elements of the pattern but rather cause these elements to develop with inappropriate identities.

Maternal–zygotic mutants

In zebrafish, maternally derived products are synthesized during oogenesis and accumulate to regulate early embryonic development. Maternal–zygotic mutants allow for systematic analysis of the maternal effects of known zygotic lethal mutations.

Neurulation

The formation of the embryonic neural plate and its transformation into the neural tube.

Neurocoel

The cavity or system of cavities in the interior of the vertebrate CNS comprising the central canal of the spinal cord and the ventricles of the brain.

Rhombomere

A segment or swelling in the vertebrate embryo that is part of the developing rhombencephalon, which will become the pons, cerebellum and medulla. The fate of a rhombomere is affected by differential expression of Hox genes.

2′O-methyl antisense oligoribonucleotides

These bind to target microRNAs to block their function by specifically inactivating the RNA interference activity associated with miRNA–protein complexes, and are stable and specific over a wide range of concentrations.

Maternal to zygotic transition

In early embryos, initial protein synthesis occurs primarily through maternal mRNAs that are synthesized during oogenesis in the mother and stored in the oocyte. Eventually the embryo undergoes a transition and transcribes its own genes.

Growth cones

A dynamic, actin-supported extension of a developing axon seeking its synaptic target.

Endochondrial ossification

Involves the conversion of a type of cartilage called hyaline cartilage to bone. Hyaline cartilage is formed into a likeness of the future bone by chondroblast cells.

Polysome

A functional unit of protein synthesis that consists of several ribosomes that are attached along the length of a single molecule of mRNA. It is the shortened form of the term polyribosome.

Internal initiation

Translation initiation occurs by an internal ribosomal-binding mechanism in contrast to ribosomal binding at the 5′ end of the mRNA, facilitated by an interaction between the methylated cap structure at the end of the mRNA and the cap-binding protein complex eIF–4F.

Glomeruli

Anatomical substructure of the Drosophila antennal lobe.

Interactome

The network of protein interactions.

Transcriptome

Historically the set of all mRNAs produced in a cell or a population of cells. However, more recently it has been suggested that the term must stipulate whether non-coding RNAs are included or not.

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Kosik, K. The neuronal microRNA system. Nat Rev Neurosci 7, 911–920 (2006). https://doi.org/10.1038/nrn2037

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