MicroRNAs in Animal Development

Abstract

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.

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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]