Search

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.02.030 Byline: Ronald H.A. Plasterk (1) Abstract: Micro RNAs (miRNAs) are [approximately equal to]22 nucleotide single-stranded noncoding RNA molecules that bind to target messenger RNAs (mRNAs) and silence their expression. This Essay explores the importance of miRNAs in animal development and their possible roles in disease and evolution. Author Affiliation: (1) Hubrecht Laboratory (KNAW), Utrecht University, 3584CT Utrecht, the Netherlands

MicroRNAs (miRNAs) control gene expression by translational inhibition and destabilization of mRNAs. While hundreds of miRNAs have been found, only a few have been studied in detail. miRNAs have been implicated in tissue morphogenesis, cellular processes like apoptosis, and major signaling pathways. Emerging evidence suggests a direct link between miRNAs and disease, and miRNA expression signatures are associated with various types of cancer. In addition, the gain and loss of miRNA target sites appears to be causal to some genetic disorders. Here, we discuss the current literature on the role of miRNAs in animal development and disease. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression by base-pairing to mRNAs. Hundreds of miRNAs have been identified in various multicellular organisms and many miRNAs are evolutionarily conserved. Although the biological functions of most miRNAs are unknown, miRNAs are predicted to regulate up to 30% of the genes within the human genome. Gradually, we are beginning to understand the functions of individual miRNAs and the general function of miRNA action. Here, we review the recent advances in miRNA biology in animals. Particularly, we focus on the roles of miRNAs in vertebrate development and disease. [Copyright &y& Elsevier]

The availability of complete genome sequences has revealed that genomes contain numerous mobile genetic elements. The activity of these transposons results in genome instability. In the nematode Caenorhabditis elegans, transposition is silenced in the germline, protecting the genome from heritable defects that are caused by transposon jumps. The discovery of RNA interference (RNAi) has greatly increased our understanding of this genome-defense mechanism because transposon silencing and RNAi share common factors. RNAi is the post-transcriptional silencing of a gene in response to double-stranded RNA (dsRNA), which is processed into small interfering RNAs (siRNAs) that mediate sequence-specific RNA degradation. Indeed, transposon-derived dsRNA and siRNAs are detected in vivo and are capable of inducing silencing. In addition, many new genes have been identified that are required for the silencing of transposons. In this article, we discuss our current model for transposon silencing and address several unanswered questions because many aspects of this protection mechanism in C. elegans might be present in a broad range of organisms. [Copyright &y& Elsevier]

Transposable elements are stretches of DNA that can move and multiply within the genome of an organism. The Caenorhabditis elegans genome contains multiple Tc1 transposons that jump in somatic cells, but are silenced in the germ line. Many mutants that have lost this silencing have also lost the ability to execute RNA interference (RNAi), a process whereby genes are suppressed by exposure to homologous double-stranded RNA (dsRNA). Here we show how RNAi causes transposon silencing in the nematode germ line. We find evidence for transposon-derived dsRNAs, in particular to the terminal inverted repeats, and show that these RNAs may derive from read-through transcription of entire transposable elements. Small interfering RNAs of Tc1 were detected. When a germline-expressed reporter gene is fused to a stretch of Tc1 sequence, this transgene is silenced in a manner dependent on functional mutator genes (mut-7, mut-16 and pk732). These results indicate that RNAi surveillance is triggered by fortuitous read-through transcription of dispersed Tc1 copies, which can form dsRNA as a result of ‘snap-back’ of the terminal inverted repeats. RNAi mediated by this dsRNA silences transposase gene expression. [ABSTRACT FROM AUTHOR]

Summary: Piwi proteins specify an animal-specific subclass of the Argonaute family that, in vertebrates, is specifically expressed in germ cells. We demonstrate that zebrafish Piwi (Ziwi) is expressed in both the male and the female gonad and is a component of a germline-specifying structure called nuage. Loss of Ziwi function results in a progressive loss of germ cells due to apoptosis during larval development. In animals that have reduced Ziwi function, germ cells are maintained but display abnormal levels of apoptosis in adults. In mammals, Piwi proteins associate with approximately 29-nucleotide-long, testis-specific RNA molecules called piRNAs. Here we show that zebrafish piRNAs are present in both ovary and testis. Many of these are derived from transposons, implicating a role for piRNAs in the silencing of repetitive elements in vertebrates. Furthermore, we show that piRNAs are Dicer independent and that their 3′ end likely carries a 2′O-Methyl modification. [Copyright &y& Elsevier]

RNA interference (RNAi) in the nematode worm, Caenorhabditis elegans, occurs systemically. Double-stranded RNA (dsRNA) provided in the diet can be absorbed from the gut lumen and distributed throughout the body, triggering RNAi in tissues that are not exposed to the initial dsRNA trigger . This is in marked contrast to other animals, in which RNAi does not spread from targeted tissues to neighboring cells . Here, we report the characterization of mutants defective in the systemic aspect of RNAi, but not in the core RNAi process itself. Analysis of these mutants suggests that dsRNA uptake is a specific process involving several unique proteins. [Copyright &y& Elsevier]

Presents a study that identified genes that protect the Caenorhabditis elegans genome against mutations by genome-wide RNAi. Method of the study; Results and discussion; Conclusion.

One of the remarkable aspects about RNA interference (RNAi) in Caenorhabditis elegans is that the trigger molecules, dsRNA, can be administered via the animal''s food. We assayed whether this feature is a universal property of the species by testing numerous strains that have been isolated from different parts of the globe. We found that one isolate from Hawaii had a defect in RNAi that was specific to the germline and was a result of multiple mutations in a PAZ/PIWI domain-containing protein, which we named PPW-1. Deleting ppw-1 in the canonical C. elegans strain Bristol N2 makes it resistant to feeding of dsRNA directed against germline-expressed genes. PPW-1 belongs to the Argonaute family of proteins, which act in posttranscriptional gene silencing and development, and is homologous to the RNAi gene rde-1. Our data indicate that at least two members of this family are required for complete and effective RNAi in C. elegans. [Copyright &y& Elsevier]

Posttranscriptional gene silencing in Caenorhabditis elegans results from exposure to double-stranded RNA (dsRNA), a phenomenon designated as RNA interference (RNAi), or from co-suppression, in which transgenic DNA Leads to silencing of both the transgene and the endogenous gene. Here we show that single-stranded RNA oligomers of antisense polarity can also be potent inducers of gene silencing. As is the case for co-suppression, antisense RNAs act independently of the RNAi genes rde-1 and rde-4 but require the mutator/RNAi gene mut-7 and a putative DEAD box RNA helicase, mut-14. Our data favor the hypothesis that gene silencing is accomplished by RNA primer extension using the mRNA as template, leading to dsRNA that is subsequently degraded. [ABSTRACT FROM AUTHOR]

Investigates the role of RNA amplification in the RNA interference in Caenorhabditis elegans. Biochemical detection of secondary small interfering RNA; Use of RNase protection assays in detecting small RNAs; Structural requirements for triggering of transitive RNA interference.