Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The roles of microRNAs in mouse development


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Winter, J., Jung, S., Keller, S., Gregory, R. I. & Diederichs, S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat. Cell Biol. 11, 228–234 (2009).

    CAS  PubMed  Google Scholar 

  2. 2.

    Agarwal, V., Bell, G. W., Nam, J. W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, e05005 (2015).

    PubMed Central  Google Scholar 

  3. 3.

    Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018). This is an expansive review of many aspects of miRNA biology.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Jonas, S. & Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421–433 (2015).

    CAS  PubMed  Google Scholar 

  5. 5.

    Wang, Y., Medvid, R., Melton, C., Jaenisch, R. & Blelloch, R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat. Genet. 39, 380–385 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).

    CAS  PubMed  Google Scholar 

  7. 7.

    Wienholds, E., Koudijs, M. J., van Eeden, F. J., Cuppen, E. & Plasterk, R. H. The microRNA-producing enzyme Dicer1 is essential for zebrafish development. Nat. Genet. 35, 217–218 (2003).

    CAS  PubMed  Google Scholar 

  8. 8.

    Giraldez, A. J. et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833–838 (2005).

    CAS  PubMed  Google Scholar 

  9. 9.

    Grishok, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34 (2001).

    CAS  PubMed  Google Scholar 

  10. 10.

    Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654–2659 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lee, Y. S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69–81 (2004).

    CAS  PubMed  Google Scholar 

  12. 12.

    Suh, N. et al. MicroRNA function is globally suppressed in mouse oocytes and early embryos. Curr. Biol. 20, 271–277 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Spruce, T. et al. An early developmental role for miRNAs in the maintenance of extraembryonic stem cells in the mouse embryo. Dev. Cell 19, 207–219 (2010).

    CAS  PubMed  Google Scholar 

  14. 14.

    Miska, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet. 3, e215 (2007).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Alvarez-Saavedra, E. & Horvitz, H. R. Many families of C. elegans microRNAs are not essential for development or viability. Curr. Biol. 20, 367–373 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Park, C. Y. et al. A resource for the conditional ablation of microRNAs in the mouse. Cell Rep. 1, 385–391 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chen, Y. W. et al. Systematic study of Drosophila microRNA functions using a collection of targeted knockout mutations. Dev. Cell 31, 784–800 (2014).

    CAS  PubMed  Google Scholar 

  18. 18.

    Amin, N. D. et al. Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. Science 350, 1525–1529 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wienholds, E. & Plasterk, R. H. MicroRNA function in animal development. FEBS Lett. 579, 5911–5922 (2005).

    CAS  PubMed  Google Scholar 

  20. 20.

    Zhao, T. et al. A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii. Genes Dev. 21, 1190–1203 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Hertel, J. et al. The expansion of the metazoan microRNA repertoire. BMC Genom. 7, 25 (2006).

    Google Scholar 

  22. 22.

    Sempere, L. F., Cole, C. N., McPeek, M. A. & Peterson, K. J. The phylogenetic distribution of metazoan microRNAs: insights into evolutionary complexity and constraint. J. Exp. Zool. B Mol. Dev. Evol. 306, 575–588 (2006).

    PubMed  Google Scholar 

  23. 23.

    Prochnik, S. E., Rokhsar, D. S. & Aboobaker, A. A. Evidence for a microRNA expansion in the bilaterian ancestor. Dev. Genes Evol. 217, 73–77 (2007).

    CAS  PubMed  Google Scholar 

  24. 24.

    Heimberg, A. M., Sempere, L. F., Moy, V. N., Donoghue, P. C. & Peterson, K. J. MicroRNAs and the advent of vertebrate morphological complexity. Proc. Natl Acad. Sci. USA 105, 2946–2950 (2008).

    CAS  PubMed  Google Scholar 

  25. 25.

    Hertel, J. & Stadler, P. F. The expansion of animal microRNA families revisited. Life 5, 905–920 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Cheng, C., Bhardwaj, N. & Gerstein, M. The relationship between the evolution of microRNA targets and the length of their UTRs. BMC Genom. 10, 431 (2009).

    Google Scholar 

  27. 27.

    Wienholds, E. et al. MicroRNA expression in zebrafish embryonic development. Science 309, 310–311 (2005).

    CAS  PubMed  Google Scholar 

  28. 28.

    Ludwig, N. et al. Distribution of miRNA expression across human tissues. Nucleic Acids Res. 44, 3865–3877 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lagos-Quintana, M. et al. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12, 735–739 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L. & Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902–1910 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 8, 93–103 (2007).

    CAS  PubMed  Google Scholar 

  32. 32.

    Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Chalfie, M., Horvitz, H. R. & Sulston, J. E. Mutations that lead to reiterations in the cell lineages of C. elegans. Cell 24, 59–69 (1981).

    CAS  PubMed  Google Scholar 

  34. 34.

    Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

    CAS  PubMed  Google Scholar 

  35. 35.

    Mansfield, J. H. et al. MicroRNA-responsive ‘sensor’ transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nat. Genet. 36, 1079–1083 (2004).

    CAS  PubMed  Google Scholar 

  36. 36.

    Mallo, M. & Alonso, C. R. The regulation of Hox gene expression during animal development. Development 140, 3951–3963 (2013).

    CAS  PubMed  Google Scholar 

  37. 37.

    Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).

    CAS  PubMed  Google Scholar 

  38. 38.

    Hornstein, E. et al. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438, 671–674 (2005).

    CAS  PubMed  Google Scholar 

  39. 39.

    Visvanathan, J., Lee, S., Lee, B., Lee, J. W. & Lee, S. K. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cheng, L. C., Pastrana, E., Tavazoie, M. & Doetsch, F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat. Neurosci. 12, 399–408 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Peng, C. et al. Termination of cell-type specification gene programs by the miR-183 cluster determines the population sizes of low-threshold mechanosensitive neurons. Development 145, dev165613 (2018).

    PubMed  Google Scholar 

  42. 42.

    Parchem, R. J. et al. miR-302 is required for timing of neural differentiation, neural tube closure, and embryonic viability. Cell Rep. 12, 760–773 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Tian, Y. et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci. Transl. Med. 7, 279ra38 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Paikari, A., C, D. B., Saw, D. & Blelloch, R. The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport. Development 144, 3731–3743 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Johnston, R. J. Jr, Chang, S., Etchberger, J. F., Ortiz, C. O. & Hobert, O. MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc. Natl Acad. Sci. USA 102, 12449–12454 (2005).

    CAS  PubMed  Google Scholar 

  46. 46.

    Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Yoo, A. S., Staahl, B. T., Chen, L. & Crabtree, G. R. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460, 642–646 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Wang, D. et al. MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway. Nat. Cell Biol. 15, 1153–1163 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Hu, W. et al. miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a. Blood 125, 2206–2216 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Song, R. et al. miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110. Nature 510, 115–120 (2014). This article illustrates a common function, cilial maturation, of the mir-34/mir-449 family across different cell types.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Fededa, J. P. et al. MicroRNA-34/449 controls mitotic spindle orientation during mammalian cortex development. EMBO J. 35, 2386–2398 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Fletcher, R. B., Das, D. & Ngai, J. Creating lineage trajectory maps via integration of single-cell RNA-sequencing and lineage tracing: integrating transgenic lineage tracing and single-cell RNA-sequencing is a robust approach for mapping developmental lineage trajectories and cell fate changes. Bioessays 40, e1800056 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Hasuwa, H., Ueda, J., Ikawa, M. & Okabe, M. miR-200b and miR-429 function in mouse ovulation and are essential for female fertility. Science 341, 71–73 (2013).

    CAS  PubMed  Google Scholar 

  54. 54.

    Tan, C. L. et al. MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 342, 1254–1258 (2013). This article illustrates an essential postnatal miRNA requirement. mir-128-2−/− mice are hyperactive as juveniles before severe seizures and death in 2–3 months.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Li, X., Cassidy, J. J., Reinke, C. A., Fischboeck, S. & Carthew, R. W. A microRNA imparts robustness against environmental fluctuation during development. Cell 137, 273–282 (2009). The authors reveal that mir-7 imparts robustness to D. melanogaster development specifically during temperature fluctuations.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Yu, D. et al. miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta. Genes Dev. 24, 1620–1633 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    PubMed  Google Scholar 

  58. 58.

    Aurora, A. B. et al. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. J. Clin. Invest. 122, 1222–1232 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).

    CAS  PubMed  Google Scholar 

  61. 61.

    Wang, H. et al. Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210. Nat. Immunol. 15, 393–401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  PubMed  Google Scholar 

  63. 63.

    Hsin, J. P., Lu, Y., Loeb, G. B., Leslie, C. S. & Rudensky, A. Y. The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types. Nat. Immunol. 19, 1137–1145 (2018). By integrating readouts of mir-155 binding and its impact on expression across different immune cells, the authors reveal the influence of cellular context on miRNA regulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Friedman, R. C., Farh, K. K., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Xu, P. et al. Regulation of gene expression by miR-144/451 during mouse erythropoiesis. Blood 133, 2518–2528 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Freimer, J. W., Hu, T. J. & Blelloch, R. Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells. eLife 7, e38014 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Nam, J. W. et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol. Cell 53, 1031–1043 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Erhard, F. et al. Widespread context dependency of microRNA-mediated regulation. Genome Res. 24, 906–919 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Shibata, M., Nakao, H., Kiyonari, H., Abe, T. & Aizawa, S. MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors. J. Neurosci. 31, 3407–3422 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).

    CAS  PubMed  Google Scholar 

  71. 71.

    Loffreda, A., Rigamonti, A., Barabino, S. M. L. & Lenzken, S. C. RNA-binding proteins in the regulation of miRNA activity: a focus on neuronal functions. Biomolecules 5, 2363–2387 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Meunier, J. et al. Birth and expression evolution of mammalian microRNA genes. Genome Res. 23, 34–45 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Baskerville, S. & Bartel, D. P. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 11, 241–247 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Mathelier, A. & Carbone, A. Large scale chromosomal mapping of human microRNA structural clusters. Nucleic Acids Res. 41, 4392–4408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Wheeler, B. M. et al. The deep evolution of metazoan microRNAs. Evol. Dev. 11, 50–68 (2009).

    CAS  PubMed  Google Scholar 

  77. 77.

    Lewis, M. A. et al. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat. Genet. 41, 614–618 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Wang, H. et al. miR-219 cooperates with miR-338 in myelination and promotes myelin repair in the CNS. Dev. Cell 40, 566–582 e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Bao, J. et al. MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway. J. Biol. Chem. 287, 21686–21698 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Concepcion, C. P. et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet. 8, e1002797 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Wu, J. et al. Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis. Proc. Natl Acad. Sci. USA 111, E2851–E2857 (2014).

    CAS  PubMed  Google Scholar 

  82. 82.

    Pinto, D. et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677–694 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Willemsen, M. H. et al. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. J. Med. Genet. 48, 810–818 (2011).

    CAS  PubMed  Google Scholar 

  84. 84.

    Crowley, J. J. et al. Disruption of the microRNA 137 primary transcript results in early embryonic lethality in mice. Biol. Psychiatry 77, e5–e7 (2015).

    CAS  PubMed  Google Scholar 

  85. 85.

    Cheng, Y. et al. Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat. Neurosci. 21, 1689–1703 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Duan, J. et al. A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder. Am. J. Hum. Genet. 95, 744–753 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Siegert, S. et al. The schizophrenia risk gene product miR-137 alters presynaptic plasticity. Nat. Neurosci. 18, 1008–1016 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yue, M. et al. MSDD: a manually curated database of experimentally supported associations among miRNAs, SNPs and human diseases. Nucleic Acids Res. 46, D181–D185 (2018).

    CAS  PubMed  Google Scholar 

  89. 89.

    Denzler, R., Agarwal, V., Stefano, J., Bartel, D. P. & Stoffel, M. Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol. Cell 54, 766–776 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Valdmanis, P. N. et al. miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression. Nat. Commun. 9, 5321 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Rissland, O. S., Hong, S. J. & Bartel, D. P. MicroRNA destabilization enables dynamic regulation of the miR-16 family in response to cell-cycle changes. Mol. Cell 43, 993–1004 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Krol, J. et al. Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell 141, 618–631 (2010).

    CAS  PubMed  Google Scholar 

  93. 93.

    De, N. et al. Highly complementary target RNAs promote release of guide RNAs from human Argonaute2. Mol. Cell 50, 344–355 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Park, J. H., Shin, S. Y. & Shin, C. Non-canonical targets destabilize microRNAs in human Argonautes. Nucleic Acids Res. 45, 1569–1583 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    de la Mata, M. et al. Potent degradation of neuronal miRNAs induced by highly complementary targets. EMBO Rep. 16, 500–511 (2015).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Sheu-Gruttadauria, J. et al. Structural basis for target-directed microRNA degradation. Mol. Cell 75, 1243–1255.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Piwecka, M. et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357, eaam8526 (2017).

    PubMed  Google Scholar 

  98. 98.

    Kleaveland, B., Shi, C. Y., Stefano, J. & Bartel, D. P. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174, 350–362 e17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Sambandan, S. et al. Activity-dependent spatially localized miRNA maturation in neuronal dendrites. Science 355, 634–637 (2017). This study reveals subcellularly localized maturation and activity of mir-181a in neuronal dendrites and spines following local stimulation.

    CAS  PubMed  Google Scholar 

  101. 101.

    Park, I. et al. Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines. Proc. Natl Acad. Sci. USA 116, 9616–9621 (2019).

    CAS  PubMed  Google Scholar 

  102. 102.

    Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Sekita, Y. et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat. Genet. 40, 243–248 (2008).

    CAS  PubMed  Google Scholar 

  105. 105.

    Ito, M. et al. A trans-homologue interaction between reciprocally imprinted miR-127 and Rtl1 regulates placenta development. Development 142, 2425–2430 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Wystub, K., Besser, J., Bachmann, A., Boettger, T. & Braun, T. miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development. PLoS Genet. 9, e1003793 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Wei, Y. et al. Multifaceted roles of miR-1s in repressing the fetal gene program in the heart. Cell Res. 24, 278–292 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Liu, N. et al. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 22, 3242–3254 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Han, Y. C. et al. An allelic series of miR-17 approximately 92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron. Nat. Genet. 47, 766–775 (2015). Genetic dissection using an allelic series of the mir-17~92 cluster reveals co-operative targeting by these distinct polycistronic miRNAs.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Wang, Y., Luo, J., Zhang, H. & Lu, J. microRNAs in the same clusters evolve to coordinately regulate functionally related genes. Mol. Biol. Evol. 33, 2232–2247 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Marco, A. Comment on “microRNAs in the same clusters evolve to coordinately regulate functionally related genes”. Mol. Biol. Evol. 36, 1843 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Olive, V., Minella, A. C. & He, L. Outside the coding genome, mammalian microRNAs confer structural and functional complexity. Sci. Signal. 8, re2 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Wang, Y. et al. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat. Genet. 40, 1478–1483 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Warth, S. C. et al. Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. EMBO J. 34, 1195–1213 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Kurata, J. S. & Lin, R. J. MicroRNA-focused CRISPR-Cas9 library screen reveals fitness-associated miRNAs. RNA 24, 966–981 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Chang, H. et al. CRISPR/cas9, a novel genomic tool to knock down microRNA in vitro and in vivo. Sci. Rep. 6, 22312 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Narayanan, A. et al. In vivo mutagenesis of miRNA gene families using a scalable multiplexed CRISPR/Cas9 nuclease system. Sci. Rep. 6, 32386 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ebert, M. S. & Sharp, P. A. MicroRNA sponges: progress and possibilities. RNA 16, 2043–2050 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Bonci, D. et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat. Med. 14, 1271–1277 (2008).

    CAS  PubMed  Google Scholar 

  120. 120.

    Gaidatzis, D., Burger, L., Florescu, M. & Stadler, M. B. Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation. Nat. Biotechnol. 33, 722–729 (2015).

    CAS  PubMed  Google Scholar 

  121. 121.

    McGeary, S. E. et al. The biochemical basis of microRNA targeting efficacy. Science 366, eaav1741 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Yang, A. et al. 3’ uridylation confers miRNAs with non-canonical target repertoires. Mol. Cell 75, 511–522.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Li, L. et al. The landscape of miRNA editing in animals and its impact on miRNA biogenesis and targeting. Genome Res. 28, 132–143 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Ke, S. et al. A majority of m6A residues are in the last exons, allowing the potential for 3’ UTR regulation. Genes Dev. 29, 2037–2053 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Bluhm, B. et al. miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage. Development 144, 3562–3577 (2017).

    CAS  PubMed  Google Scholar 

  126. 126.

    Faridani, O. R. et al. Single-cell sequencing of the small-RNA transcriptome. Nat. Biotechnol. 34, 1264–1266 (2016).

    CAS  PubMed  Google Scholar 

  127. 127.

    Nowakowski, T. J. et al. Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development. Nat. Neurosci. 21, 1784–1792 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Wang, N. et al. Single-cell microRNA-mRNA co-sequencing reveals non-genetic heterogeneity and mechanisms of microRNA regulation. Nat. Commun. 10, 95 (2019).

    PubMed  PubMed Central  Google Scholar 

Download references


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.

Author information




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.

Corresponding author

Correspondence to Robert Blelloch.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Genetics thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information


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.


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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

DeVeale, B., Swindlehurst-Chan, J. & Blelloch, R. The roles of microRNAs in mouse development. Nat Rev Genet 22, 307–323 (2021).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing