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MicroRNA control of signal transduction

Key Points

  • Signal transduction pathways are prime candidates for microRNA (miRNA)-mediated regulation: the highly dynamic and dose-sensitive signalling complexes are the ideal targets for the degree of quantitative regulation imposed by miRNAs.

  • Each cell type expresses a unique set of miRNAs, allowing it to interpret the extracellular signals according to its history and environment, leading to the activation of genes that better suit its needs: a process called context-dependent gene expression.

  • Some signalling pathways are kept actively repressed in the absence of stimulation. This default repression mechanism ensures that target genes are activated only in the presence of a signal. miRNAs contribute to this control, inhibiting the expression of transcripts that are either leaky from transcriptional control or that must be expressed at low levels.

  • A miRNA can be regulated by a signalling pathway and, in turn, target a component of another pathway: in doing so, the miRNA can serve as a mediator of crosstalk between signalling pathways, coordinating their activity.

  • miRNAs are part of signalling networks. By buffering environmental and genetic fluctuations, they confer robustness to the cellular response to extracellular signals.

  • Signalling pathways can control the biogenesis of specific miRNAs at the level of processing. Signalling mediators have been shown to be part of miRNA-processing complexes, tuning miRNA maturation.

Abstract

MicroRNAs (miRNAs) are integral elements in the post-transcriptional control of gene expression. After the identification of hundreds of miRNAs, the challenge is now to understand their specific biological function. Signalling pathways are ideal candidates for miRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Indeed, emerging evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-β, WNT, Notch and epidermal growth factor. As such, miRNAs serve as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.

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Figure 1: MicroRNAs in context-dependent transcriptional activation and default repression.
Figure 2: MicroRNAs and signalling gradients.
Figure 3: MicroRNAs in signalling crosstalk and coordination.
Figure 4: MicroRNAs in networks and loops.
Figure 5: MicroRNAs in signalling networks.

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Acknowledgements

We thank the members of the S.P. laboratory for thoughtful insights. We apologize to those whose work could not be cited owing to space limitations. We thank O. Wessely for comments and insights on the manuscript. Our miRNA work is supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC), Comitato Promotere Telethon, Cariparo Foundation (excellence grant), University of Padua (strategic grant) to S.P., by the Ministery of Health (Giovani Ricercatori) to G.M. and by a Uehara Foundation and Marie Curie International fellowship to M.I.

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DATABASES

miRNA database

 bantam

let-7

miR-7

miR-8

miR-21

miR-26a

miR-126

miR-145

miR-192

miR-203

miR-217

miR-278

miR-290

miR-430

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Glossary

Haploinsufficient

A gene that requires biallelic expression. Suppression of one allele would reduce the gene dosage below the crucial level.

Cerebellar granule progenitor cell

A cell that is located in the outermost layer of the cerebellar cortex in newborns and that generates the most abundant type of neuron of the mammalian brain.

Medulloblastoma

A highly malignant primary brain tumour that originates in the cerebellum.

Hypomorphic

A mutation that reduces, but does not completely eliminate, the function of a gene.

Spemann's organizer

The portion of the amphibian embryo (dorsal blastopore lip, corresponding to the node of mammalian and avian embryos) endowed with the capacity to induce a secondary body after transplantation into a host embryo.

Gliomagenesis

Emergence of a tumour that arises from glial cells in the brain or spinal cord.

Glomerular mesangial cell

A component of the renal glomerulus that can contract and relax and secrete inflammatory cytokines.

Basal layer

The deepest layer of pluristratified epithelia, which are attached to the basement membrane and enriched in stem or transient amplifying progenitor cells.

Suprabasal

The layer of cells in mammalian epithelia that are located just above the deepest (or basal) layer, typically generated by the asymmetric cell division of basally located stem cells.

Nucleosome

The fundamental packing unit of the eukaryotic chromatin, consisting of DNA wrapped around the histone octamer.

Uridylation

Enzymatic reaction leading to the addition of uridine nucleoside to the 3′ end of a miRNA strand.

AntagomiR and locked nucleic acid

Chemically engineered synthetic oligonucleotides that are complementary to the specific miRNA target, with modifications to make it more resistant to degradation to optimize silencing of endogenous miRNAs.

Multivesicular body

An endocytic intermediate organelle in the lysosomal degradative pathway that contains small vesicles and is surrounded by a limiting membrane.

Exosome

A small vesicle that is secreted by a wide range of cell types and that consists of a lipid raft embedded with components of the original cell membrane that can be shuttled to a different cell.

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Inui, M., Martello, G. & Piccolo, S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 11, 252–263 (2010). https://doi.org/10.1038/nrm2868

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