A major function of microRNAs is to inhibit messenger RNA (mRNA) translation by binding to a specific 3’ untranslated region (UTR) through sequence complementation. In a recent study published in the March 2012 issue of Cell Stem Cell, Boutet et al. discovered that Pax3 transcripts in muscle stem cells in vivo can have both long and short 3’UTRs, an effect controlled by differential poly-adenylation patterns during the course of development. While Pax3 transcripts with long 3’UTRs are susceptible to translational inhibition by miR-206, transcripts with short 3’UTR are profoundly resistant to miR-206.
About Pax3: Pax3 is a transcription factor that maintains the proliferative population of syndecan4-positive muscle stem cells and progenitors, and inhibits differentiation. Pax3 expression occurs at E10.5-E15.5 of the developing embryo, and is translationally inhibited by miR-206 during muscle cell differentiation. In the adult, Pax3 is expressed in QSCs, where it plays an important role in maintaining and expanding the QSC population (Boutet et al., 2007, 2010). Lastly, as confirmed in this paper, Pax3 knockdown with siRNA markedly reduced the number of syndecan4-positive QSCs in muscle fiber explants derived from skeletal and diaphragm muscle explants.
MiR-206 Resistant Pax3 Transcripts in Muscle Stem Cells: Interestingly, the authors found that miR-206-resistant Pax3 transcripts bearing the short 3’UTRs are expressed predominantly in QSCs residing in adult mouse diaphragm muscles, and in developing muscles in mouse embryos at E10.5-11.5 (embryonic day 10.5-11.5). In contrast, QSCs from adult skeletal muscle fibers expressed predominantly the long-3’UTR Pax3 transcripts that are susceptible to miR-206 inhibition. While the level of Pax3 expression in skeletal QSCs is profoundly regulated by changes in miR-206 expression, the level of Pax3 expression in the diaphragm and embryonic derived QSCs remains constant regardless of miR-206 expression levels. Functionally, while miR-206 inhibition resulted in Pax3- mediated expansion of the Syndecan4-positive satellite population in skeletal muscles, the same treatment in diaphragm and embryonic derived QSCs had no effect.
Significance- from the Scientist’s Point of View: This discovery has enormous impact on current cell research, where microRNAs often take center stage in our efforts to elucidate the molecular events behind cell behavior, and in a broader sense, the mechanisms behind cancers and developmental diseases. The fact that poly-adenylation can alter translational inhibition of mRNA transcripts has changed our simplistic concept of how microRNAs work to control protein translation, and fostered caution in the interpretation of recent literature or data on how microRNAs contribute to diseases.
Boutet et al. Cell Stem Cell 10, 327–336, March 2, 2012
Boutet, S.C., Disatnik, M.H., Chan, L.S., Iori, K., and Rando, T.A. (2007).Cell 130, 349–362.
Boutet, S.C., Biressi, S., Iori, K., Natu, V., and Rando, T.A. (2010). Mol. Cell 40, 749
Evading MicroRNA Control By Differential Poly-Adenylation Patterns-
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