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The roles of microRNAs in mouse development

Abstract

Hundreds of microRNAs (miRNAs) are expressed in distinct spatial and temporal patterns during embryonic and postnatal mouse development. The loss of all miRNAs through the deletion of critical miRNA biogenesis factors results in early lethality. The function of each miRNA stems from their cumulative negative regulation of multiple mRNA targets expressed in a particular cell type. During development, miRNAs often coordinate the timing and direction of cell fate transitions. In adults, miRNAs frequently contribute to organismal fitness through homeostatic roles in physiology. Here, we review how the recent dissection of miRNA-knockout phenotypes in mice as well as advances related to their targets, dosage, and interactions have collectively informed our understanding of the roles of miRNAs in mammalian development and adaptive responses.

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Fig. 1: The developmental stage of miRNA functions.
Fig. 2: miRNAs regulate developmental timing.
Fig. 3: miRNAs coordinate cell fate decisions.
Fig. 4: miRNAs buffer against environmental perturbations.
Fig. 5: miRNA targeting is affected by cellular context.
Fig. 6: MicroRNA phenotypes can be dose-dependent.
Fig. 7: Regulatory network of neuronal non-coding regulatory RNAs.
Fig. 8: miRNAs with distinct seed sequences cooperate during development.

Data availability

The authors declare that data supporting the figures in this study are available in the article and the Supplementary Information. The full source data for Fig. 1 are provided in Supplementary Tables 1 and 2.

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Acknowledgements

B.D. and R.B. were or are supported by a CIHR Fellowship, NICHD R21 (R21HD093084), NICHD P50 (P50HD055764) and NIGMS R01s (R01GM122439 and R01GM125089). The authors also thank F. Chanut for providing feedback on the manuscript.

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B.D. and J.S.C. researched the literature. B.D. and R.B. contributed substantially to discussions of the content. B.D. wrote the article. R.B. reviewed and/or edited the manuscript before submission.

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Correspondence to Robert Blelloch.

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Supplementary information

Glossary

Seed sequence

Nucleotides 2–7 of microRNAs, which largely determine the target binding repertoire of microRNAs.

Purifying selection

The selective removal of deleterious alleles by natural selection.

Developmental timing

The schedule of events during development of unperturbed organisms.

Heterochronic

Unsynchronized events relative to the expected schedule.

miRNA cluster

Multiple microRNAs (miRNAs) that are physically adjacent in the genome.

miRNA family

MicroRNAs (miRNAs) encoded by distinct genomic loci with common seed sequences.

Target suppression

Destabilization, translational inhibition or cleavage of RNAs bound by microRNAs.

Synergistic targeting

Target suppression that exceeds the additive suppression of multiple microRNAs.

Heterotypic cluster

A microRNA cluster that encodes microRNAs from more than one seed family.

Cooperative targeting

Distinct microRNAs additively suppressing a common target.

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DeVeale, B., Swindlehurst-Chan, J. & Blelloch, R. The roles of microRNAs in mouse development. Nat Rev Genet 22, 307–323 (2021). https://doi.org/10.1038/s41576-020-00309-5

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