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  • ANRV274-PP57-02 ARI 5 April 2006 18:55

    MicroRNAs and TheirRegulatory Roles in PlantsMatthew W. Jones-Rhoades,1 David P. Bartel,1

    and Bonnie Bartel21Whitehead Institute for Biomedical Research, Department of Biology, MassachusettsInstitute of Technology, and Howard Hughes Medical Institute, Cambridge,Massachusetts 02142; email: dbartel@wi.mit.edu2Department of Biochemistry and Cell Biology, Rice University, Houston,Texas 77005; email: bartel@rice.edu

    Annu. Rev. Plant Biol.2006. 57:1953

    The Annual Review ofPlant Biology is online atplant.annualreviews.org

    doi: 10.1146/annurev.arplant.57.032905.105218

    Copyright c 2006 byAnnual Reviews. All rightsreserved

    First published online as aReview in Advance onJanuary 30, 2006

    1543-5008/06/0602-0019$20.00

    Key Words

    noncoding RNAs, post-transcriptional gene regulation, plantdevelopment, RNA silencing

    AbstractMicroRNAs (miRNAs) are small, endogenous RNAs that regu-late gene expression in plants and animals. In plants, these 21-nucleotide RNAs are processed from stem-loop regions of longprimary transcripts by a Dicer-like enzyme and are loaded intosilencing complexes, where they generally direct cleavage of com-plementary mRNAs. Although plant miRNAs have some con-served functions extending beyond development, the importanceof miRNA-directed gene regulation during plant development isnow particularly clear. Identified in plants less than four years ago,miRNAs are already known to play numerous crucial roles at eachmajor stage of developmenttypically at the cores of gene regula-tory networks, targeting genes that are themselves regulators, suchas those encoding transcription factors and F-box proteins.

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    Contents

    INTRODUCTION. . . . . . . . . . . . . . . . . 20GENOMICS OF PLANT

    MICRORNAs . . . . . . . . . . . . . . . . . . . 21MicroRNA Gene Discovery:

    Cloning . . . . . . . . . . . . . . . . . . . . . . . 21MicroRNA Gene Discovery:

    Genetics . . . . . . . . . . . . . . . . . . . . . . 22MicroRNA Gene Discovery:

    Bioinformatics . . . . . . . . . . . . . . . . 23The Conserved MicroRNAs in

    Plants . . . . . . . . . . . . . . . . . . . . . . . . . 25Nonconserved MicroRNAs and

    the Challenges of DefinitiveMicroRNA Classification . . . . . . 27

    MICRORNA BIOGENESIS . . . . . . . . 28Transcription of MicroRNA

    Precursors . . . . . . . . . . . . . . . . . . . . 28MicroRNA Processing and

    Export . . . . . . . . . . . . . . . . . . . . . . . . 29MicroRNA Incorporation into the

    Silencing Complex . . . . . . . . . . . . 31Plant MicroRNA Expression . . . . . . 32

    MECHANISMS OF MICRORNAFUNCTION . . . . . . . . . . . . . . . . . . . . 33MicroRNA-Directed RNA

    Cleavage . . . . . . . . . . . . . . . . . . . . . . 33Additional Mechanisms of

    MicroRNA-DirectedRepression . . . . . . . . . . . . . . . . . . . . 33

    Small RNA-DirectedTranscriptional Silencing . . . . . . 34

    REGULATORY ROLES OFPLANT MICRORNAs. . . . . . . . . . . 35Identification of Plant MicroRNA

    Targets . . . . . . . . . . . . . . . . . . . . . . . 35The Scope of

    MicroRNA-MediatedRegulation in Plants . . . . . . . . . . . 35

    Experimental Confirmation ofPlant MicroRNA Targets . . . . . . 36

    Regulatory Roles of PlantMicroRNAs . . . . . . . . . . . . . . . . . . . 38

    MICRORNAs: PLANTS VERSUSANIMALS . . . . . . . . . . . . . . . . . . . . . . . 43

    INTRODUCTION

    Multicellular organisms depend on complexnetworks of gene regulatory pathways. Mi-croRNAs (miRNAs), which went unnoticeduntil recently, are key components of thesenetworks. Initially discovered as regulators ofdevelopmental timing in Caenorhabditis elegans(67, 114), miRNAs are now known to play avariety of important regulatory roles in bothplants and animals.

    MicroRNAs are short, endogenouslyexpressed, nontranslated RNAs that are pro-cessed by Dicer-like proteins from stem-loop regions of longer RNA precursors(Figure 1, reviewed in 13). MicroRNAsare chemically and functionally similar tosmall interfering RNAs (siRNAs, see SmallInterfering RNAs sidebar), which can me-diate the related phenomena of RNA in-terference (RNAi), post-transcriptional genesilencing (PTGS), and transcriptional genesilencing (TGS). Like miRNAs, siRNAs areprocessed by the Dicer RNaseIII family ofenzymes, but instead of deriving from localstem-loop structures, siRNAs are processedfrom long, double-stranded precursors (eitherfrom much longer stems or from bimolecularduplexes). Both miRNAs and siRNAs are in-corporated into silencing complexes that con-tain Argonaute proteins, wherein they canguide repression of target genes.

    Although miRNAs are deeply conservedwithin both the plant and animal king-doms, there are substantial differences be-tween the two lineages with regard to themechanism and scope of miRNA-mediatedgene regulation; several of these differenceshave been instrumental in the rapid increasein understanding of plant miRNA biology.Plant miRNAs are highly complementary toconserved target mRNAs, which allows fastand confident bioinformatic identification ofplant miRNA targets (53, 116). As expectedfrom this extensive complementarity to their

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  • ANRV274-PP57-02 ARI 5 April 2006 18:55

    targets, plant miRNAs guide cleavage of theirtargets, an activity readily assayed in vitroand in vivo, which allows facile confirmationof predicted targets (55, 79, 128). In ad-dition, Arabidopsis is a genetically tractablemodel organism, which enables study ofthe genetic pathways that underlie miRNA-mediated regulation and the phenotypic con-sequences of perturbing miRNA-mediatedgene regulation. In this review, we describethe flurry of exciting results revealing the bi-ological functions of these tiny riboregulatorsthat have been made possible by the conver-gence of these factors.

    GENOMICS OF PLANTMICRORNAs

    MicroRNA Gene Discovery: Cloning

    MicroRNAs have been discovered using threebasic approaches: direct cloning, forward ge-netics, and bioinformatic prediction followedby experimental validation. The most directmethod of miRNA discovery is to isolate andclone small RNAs from biological samples,and several groups have used this approachto identify small plant RNAs (78, 92, 107,115, 125, 127, 143). The cloning methodswere adapted from those first used to identifylarge numbers of animal miRNAs (62, 64) andinvolve isolating small RNAs, ligating adap-tor oligonucleotides, reverse transcription,amplification, and sequencing. Some proto-cols incorporate methods to enrich for Dicercleavage products (i.e., molecules with 5

    phosphates and 3 hydroxyls) and to concate-merize the short cDNAs so that several canbe identified in a single sequencing read (64).The initial cloning experiments in Arabidop-sis identified 19 miRNAs, which fell into 15families (78, 92, 107, 115), although the hun-dreds of other small RNAs also cloned, whichincluded degradation fragments and endoge-nous siRNAs, sometimes complicated classi-fication of the miRNAs. Subsequent cloningexperiments have expanded our knowledge ofsmall RNAs in Arabidopsis (127, 141, 142),

    SMALL INTERFERING RNAs

    siRNAs were first observed in plants (47), and in Arabidopsis,most small RNAs are siRNAs (78, 115, 127, 141, 142). Theyare implicated in a variety of processes, including defenseagainst viruses, establishment of heterochromatin, silencingof transposons and transgenes, and post-transcriptional regu-lation of mRNAs (reviewed in 15). MicroRNAs and siRNAshave much in common (Figure 1). Both are 2024 nucleotideslong and processed from longer RNA precursors by Dicer-likeribonucleases (19, 44, 47, 48, 52, 67, 147a), and both are incor-porated into ribonucleoprotein silencing complexes in whichthe small RNAs, through their base-pairing potential, guidetarget gene repression (37, 48, 67, 96a, 138, 147a).

    The fundamental difference between the two small RNAclasses is the nature of their precursors; siRNAs are pro-cessed from long, double-stranded RNAs (37, 147a), whereasmiRNAs are processed from single RNA molecules that in-clude an imperfect stem-loop secondary structure (62, 64,66, 115). Several additional characteristics distinguish mostmiRNAs from most siRNAs. Many miRNAs are conservedbetween related organisms, whereas most endogenously ex-pressed siRNAs are not (62, 64, 66, 115). Many (but not all)siRNAs target the gene from which they are derived or veryclosely related genes. In contrast, miRNAs regulate genesunrelated to loci encoding the miRNAs. In fact, the imper-fect base pairing in the miRNA precursor stem-loop mayhelp prevent the miRNA locus from undergoing silencing bythe miRNA that it encodes. Finally, although the proteinsrequired for siRNA and miRNA biogenesis are related andsometimes overlap, the genetic requirements for miRNA andsiRNA function are partially distinct in many orga

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