MicroRNAs in Animal Development


Micro ribonucleic acids (miRNAs) are small, noncoding RNAs that regulate gene expression, usually via posttranscriptional repression. Most animal genomes encode hundreds of miRNAs, which cumulatively regulate thousands of messenger RNA (mRNA) targets. miRNAs are required for animal development, and are integrated into genetic pathways that govern cell fates, behaviours, tissue patterning and differentiation. In these roles, miRNAs often regulate multiple targets in the same cell, from global regulators of gene expression to structural proteins and enzymes. Not surprisingly, miRNAs are expressed in a variety of patterns and tissue types in developing embryos, and this differential expression is controlled at many levels. miRNA–target interactions also have diverse functions, from rapidly silencing genes, such as during lineage progression, to reinforcing the silencing of genes regulated by transcriptional mechanisms, to quantitatively tuning the levels of target protein expression.

Key Concepts

  • The process of development requires fine control of differential expression of genes.

  • MicroRNAs (miRNAs) are small, noncoding transcripts that bind target mRNAs and regulate their expression.

  • Each miRNA can regulate hundreds of mRNA targets, and most animal mRNAs are regulated by one or more miRNAs.

  • miRNAs can regulate cellular differentiation states through targeting multiple processes at once.

  • The expression of miRNAs is highly regulated during development.

  • miRNAs are essential for animal development, and play roles in most developmental processes.

Keywords: microRNA; development; differentiation; patterning; embryogenesis

Figure 1.

MicroRNAs are differentially expressed during animal development, shown here by RNA in situ hybridizations in chick embryos. (a) miR‐1 is expressed in the developing heart and skeletal muscle. (b) miR‐124 is expressed in the developing brain and spinal cord. (c) miR‐205b expression is highest in the limb buds. Reproduced with permission from P.B. Antin, http://geisha.arizona.edu/geisha/, and see also Darnell et al..

Figure 2.

miR‐124 regulates neuronal differentiation at many levels. Targets in embryonic and adult neural progenitors include global regulators of gene expression profiles including transcription factors, chromatin‐modifying proteins, splicing factors and signalling proteins. miR‐124 also regulates targets directly involved in neuronal morphogenesis and function. All targets shown are validated in rodents, except Caspase9 and Apaf1 (Xenopus) and Integrin β1 and Laminin (chick). *The direct miR‐124 targets in cytoskeletal regulation have not been determined.

Figure 3.

Gene structure and regulation of vertebrate miRNAsmiR‐1, miR‐133 and miR‐206. (a) These miRNAs are expressed as bicistronic RNAs transcribed from three loci (i–iii). Enhancers are depicted as black bars, and miRNA precursors as hairpin structures. The miR‐1 containing clusters (i and ii) are expressed in heart and skeletal muscle, and the miR‐206 cluster (iii) is expressed only in skeletal muscle. Each enhancer drives a subtly different pattern expression, but all are regulated by combinations of myogenic factors including mef2, MyoD and SRF. This, along with alternative splicing, likely affords precise regulation of dosage of each miRNA. (b) The miR‐1 and mef2 interaction likely drives muscle differentiation forward by upregulating expression of both. mef2, a myogenic factor that promotes muscle cell fates, activates miR‐1, which represses expression of precursor genes. Among many targets, miR‐1 represses HDAC4, leading to enhanced mef2 expression in a positive feedback loop. (c) In another type of regulation, miR‐133 represses the myogenic factor SRF, which activates it. This likely has the effect of fine tuning and stabilizing the expression levels of both factors (see text). Modified from Williams et al., with permission from Elsevier.

Figure 4.

Hox embedded miRNAs regulate HoxmRNA expression. (a) Mouse Hox clusters showing protein‐coding genes and the miRNA families, miR‐10 and miR‐196. Predicted Hox targets of these miRNAs are shown (solid lines: conserved from mouse to human and dashed lines: mouse only). Checks indicate experimentally validated targets in mouse or zebrafish (see text). (Modified from Yekta et al., with permission from Nature Publishing Group). (b) The DrosophilaHom cluster including protein‐coding Hox genes and the miR‐10 and iab‐4miRNAs. iab‐4 and iab‐4AS result from sense and antisense transcription through separate promoters. Predicted Hox targets of these miRNAs are shown; checks indicate experimentally validated targets. Modified from Stark et al., with permission from Cold Spring Harbour Laboratory Press.



Aboobaker AA, Tomancak P, Patel N, Rubin GM and Lai EC (2005) Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proceedings of the National Academy of Sciences of the USA 102(50): 18017–18022.

Ason B, Darnell DK, Wittbrodt B et al. (2006) Differences in vertebrate microRNA expression. Proceedings of the National Academy of Sciences of the USA 103(39): 14385–14389.

Banerjee D and Slack F (2002) Control of developmental timing by small temporal RNAs: a paradigm for RNA‐mediated regulation of gene expression. BioEssays 24(2): 119–129.

Bartel D and Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Reviews Genetics 5: 396–400.

Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2): 215–233.

Bender W (2008) MicroRNAs in the Drosophila bithorax complex. Genes & Development 22(1): 14–19.

Bernstein E, Kim SY, Carmell MA et al. (2003) Dicer is essential for mouse development. Nature Genetics 35(3): 215–217.

Brennecke J, Stark A, Russell RB and Cohen SM (2005) Principles of microRNA–target recognition. PLoS Biology 3(3): e85.

Cao X, Pfaff SL and Gage FH (2007) A functional study of miR‐124 in the developing neural tube. Genes & Development 21(5): 531–536.

Carthew RW and Sontheimer EJ (2009) Origins and Mechanisms of miRNAs and siRNAs. Cell 136(4): 642–655.

Chen JF, Mandel EM, Thomson JM et al. (2006) The role of microRNA‐1 and microRNA‐133 in skeletal muscle proliferation and differentiation. Nature Genetics 38(2): 228–233.

Cheng LC, Pastrana E, Tavazoie M and Doetsch F (2009) miR‐124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neuroscience 12(4): 399–408.

Conaco C, Otto S, Han JJ and Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the USA 103(7): 2422–2427.

Darnell DK, Kaur S, Stanislaw S et al. (2006) MicroRNA expression during chick embryo development. Developmental Dynamics 235(11): 3156–3165.

Farh KK‐H, Grimson A, Jan C et al. (2005) The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310(5755): 1817–1821.

Friedman RC, Farh KK, Burge CB and Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Research 19(1): 92–105.

Giraldez AJ, Cinalli RM, Glasner ME et al. (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308(5723): 833–838.

Grishok A, Pasquinelli AE, Conte D et al. (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106: 23–24.

Harfe BD (2005) The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proceedings of the National Academy of Sciences of the USA 102(31): 10898–10903.

Harris KS, Zhang Z, McManus MT, Harfe BD and Sun X (2006) Dicer function is essential for lung epithelium morphogenesis. Proceedings of the National Academy of Sciences of the USA 103(7): 2208–2213.

Hornstein E, Mansfield JH, Yekta S et al. (2005) The microRNA miR‐196 acts upstream of Hoxb8 and Shh in limb development. Nature 438(7068): 671–674.

Hornstein E and Shomron N (2006) Canalization of development by microRNAs. Nature Genetics 38(suppl.): S20–S24.

Ketting RF, Fischer SE, Bernstein E et al. (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes & Development 15: 2654–2659.

Kloosterman WP, Wienholds E, de Bruijn E, Kauppinen S and Plasterk RH (2006) In situ detection of miRNAs in animal embryos using LNA‐modified oligonucleotide probes. Nature Methods 3(1): 27–29.

Krichevsky AM, Sonntag KC, Isacson O and Kosik KS (2006) Specific microRNAs modulate embryonic stem cell‐derived neurogenesis. Stem Cells 24(4): 857–864.

Kwon C, Han Z, Olson EN and Srivastava D (2005) MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proceedings of the National Academy of Sciences of the USA 102(52): 18986–18991.

Lagos‐Quintana M, Rauhut R, Meyer J, Borkhardt A and Tuschl T (2003) New microRNAs from mouse and human. RNA 9(2): 175–179.

Lagos‐Quintana M, Rauhut R, Yalcin A et al. (2002) Identification of tissue‐specific microRNAs from mouse. Current Biology 12(9): 735–739.

Lim LP, Lau NC, Garrett‐Engele P et al. (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027): 769–773.

Liu N, Williams AH, Kim Y et al. (2007) An intragenic MEF2‐dependent enhancer directs muscle‐specific expression of microRNAs 1 and 133. Proceedings of the National Academy of Sciences of the USA 104(52): 20844–20849.

Makeyev EV, Zhang J, Carrasco MA and Maniatis T (2007) The MicroRNA miR‐124 promotes neuronal differentiation by triggering brain‐specific alternative pre‐mRNA splicing. Molecular Cell 27(3): 435–448.

Mansfield JH, Harfe BD, Nissen R et al. (2004) MicroRNA‐responsive ‘sensor’ transgenes uncover Hox‐like and other developmentally regulated patterns of vertebrate microRNA expression. Nature Genetics 36(10): 1079–1083.

McGlinn E, Yekta S, Mansfield JH et al. (2009) In ovo application of antagomiRs indicates a role for miR‐196 in patterning the chick axial skeleton through Hox gene regulation. Proceedings of the National Academy of Sciences of the USA 106(44): 18610–18615.

Miska EA, Alvarez‐Saavedra E, Abbott AL et al. (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genetics 3(12): e215.

O'Rourke JR, Georges SA, Seay HR et al. (2007) Essential role for Dicer during skeletal muscle development. Developmental Biology 311(2): 359–368.

Rao PK, Kumar RM, Farkhondeh M, Baskerville S and Lodish HF (2006) Myogenic factors that regulate expression of muscle‐specific microRNAs. Proceedings of the National Academy of Sciences of the USA 103(23): 8721–8726.

Ronshaugen M, Biemar F, Piel J, Levine M and Lai EC (2005) The Drosophila microRNA iab‐4 causes a dominant homeotic transformation of halteres to wings. Genes & Development 19(24): 2947–2952.

Rosenberg MI, Georges SA, Asawachaicharn A, Analau E and Tapscott SJ (2006) MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR‐206. Journal of Cell Biology 175: 77–85.

Sehm T, Sachse C, Frenzel C and Echeverri K (2009) miR‐196 is an essential early stage regulator of tail regeneration, upstream of key spinal cord patterning events. Developmental Biology 126(Suppl. 1): S291–S292.

Sempere LF, Cole CN, McPeek MA and Peterson KJ (2006) The phylogenetic distribution of metazoan microRNAs: insights into evolutionary complexity and constraint. Journal of Experimental Zoology, Part B. Molecular and Developmental Evolution 306(6): 575–588.

Shkumatava A, Stark A, Sive H and Bartel DP (2009) Coherent but overlapping expression of microRNAs and their targets during vertebrate development. Genes & Development 23(4): 466–481.

Sokol NS and Ambros V (2005) Mesodermally expressed Drosophila microRNA‐1 is regulated by Twist and is required in muscles during larval growth. Genes & Development 19(19): 2343–2354.

Stark A, Brennecke J, Bushati N, Russell RB and Cohen SM (2005) Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123(6): 1133–1146.

Stark A, Bushati N, Jan CH et al. (2008) A single Hox locus in Drosophila produces functional microRNAs from opposite DNA strands. Genes & Development 22(1): 8–13.

Visvanathan J, Lee S, Lee B et al. (2007). The microRNA miR‐124 antagonizes the anti‐neural REST/SCP1 pathway during embryonic CNS development. Genes & Development 21(7): 744–749.

Walker JC and Harland RM (2009) microRNA‐24a is required to repress apoptosis in the developing neural retina. Genes & Development 23(9): 1046–1051.

Wheeler BM, Heimberg AM, Moy VN et al. (2009) The deep evolution of metazoan microRNAs. Evolution & Development 11(1): 50–68.

Williams AH, Liu N, van Rooij E and Olson EN (2009) microRNA control of muscle development and disease. Current Opinion in Cell Biology 21: 461–469.

Woltering JM and Durston AJ (2008) MiR‐10 represses HoxB1a and HoxB3a in zebrafish. PLoS One 3(1): e1396.

Yekta S, Shih IH and Bartel DP (2004) MicroRNA‐directed cleavage of HOXB8 mRNA. Science 304(5670): 594–596.

Yekta S, Tabin CJ and Bartel DP (2008) MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nature Review. Genetics 9(10): 789–796.

Yoo AS, Staahl BT, Chen L and Crabtree GR (2009) MicroRNA‐mediated switching of chromatin‐remodelling complexes in neural development. Nature 460(7255): 642–U112.

Yu JY, Chung KH, Deo M, Thompson RC and Turner DL (2008) MicroRNA miR‐124 regulates neurite outgrowth during neuronal differentiation. Experimental Cell Research 314(14): 2618–2633.

Zhao Y, Samal E and Srivastava D (2005) Serum response factor regulates a muscle‐specific microRNA that targets Hand2 during cardiogenesis. Nature 436(7048): 214–220.

Further Reading

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

Brock HW, Hodgson JW, Petruk S and Mazo A (2009) regulatory noncoding RNAs at Hox loci. Biochemical Cell Biology 87(1): 27–34.

Carthew RW (2006) Gene regulation by microRNAs. Current Opinion in Genetics and Development 16(2): 203–208.

Kloosterman WP and Plasterk RHA (2006) the diverse functions of microRNAs in animal development and disease. Developmental Cell 11(4): 441–450.

Liu C and Zhao X (2009) microRNAs in adult and embryonic neurogenesis. Neuromolecular Medicine 11(3): 141–152.

Shomron N, Golan D and Hornstein E (2009) An evolutionary perspective of animal microRNAs and their targets. Journal of Biomedicine & Biotechnology 2009: 594738.

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Mansfield, Jennifer H(Mar 2010) MicroRNAs in Animal Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021489]