The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation

Deciphering the mechanisms underlying skeletal muscle-cell differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20–25 base pair) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms and in mammals. miRNAs modulate gene expression by affecting mRNA translation or stability. In lower organisms, miRNAs are essential for cell differentiation during development; some miRNAs are involved in maintenance of the differentiated state. Here, we show that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal-muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype — even when they are not expressed in the corresponding fully differentiated tissue.

[1]  A. Kuroiwa,et al.  Coordinated expression of Hoxa-11 and Hoxa-13 during limb muscle patterning. , 1998, Development.

[2]  E. Füchtbauer,et al.  MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[3]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[4]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[5]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

[6]  Phillip A Sharp,et al.  siRNAs can function as miRNAs , 2003 .

[7]  M Velleca,et al.  Type 2X-myosin heavy chain is coded by a muscle fiber type-specific and developmentally regulated gene , 1993, The Journal of cell biology.

[8]  R. Giegerich,et al.  Fast and effective prediction of microRNA/target duplexes. , 2004, RNA.

[9]  M. Monden,et al.  Expression profiles of 39 HOX genes in normal human adult organs and anaplastic thyroid cancer cell lines by quantitative real-time RT-PCR system. , 2004, Experimental cell research.

[10]  V. Ambros,et al.  Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation , 2004, Genome Biology.

[11]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[12]  Thomas Tuschl,et al.  Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. , 2004, RNA.

[13]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[14]  W. Filipowicz,et al.  Inhibition of Translational Initiation by Let-7 MicroRNA in Human Cells , 2005, Science.

[15]  T. Hökfelt,et al.  Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Wengel,et al.  LNA (Locked Nucleic Acid): An RNA Mimic Forming Exceedingly Stable LNA:LNA Duplexes , 1998 .

[17]  S. Potter,et al.  Hoxa11 and Hoxd11 regulate branching morphogenesis of the ureteric bud in the developing kidney. , 2001, Development.

[18]  M. Rudnicki,et al.  Wnt Signaling Induces the Myogenic Specification of Resident CD45+ Adult Stem Cells during Muscle Regeneration , 2003, Cell.

[19]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[20]  P. Sharp,et al.  Embryonic stem cell-specific MicroRNAs. , 2003, Developmental cell.

[21]  S. Potter,et al.  Homeotic transformations and limb defects in Hox A11 mutant mice. , 1993, Genes & development.

[22]  T. Deacon,et al.  Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. , 1996, Cell transplantation.

[23]  Konstantin Khrapko,et al.  A microRNA array reveals extensive regulation of microRNAs during brain development. , 2003, RNA.

[24]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[25]  V. Ambros.  microRNAs Tiny Regulators with Great Potential , 2001, Cell.

[26]  T. Tuschl,et al.  Identification of Tissue-Specific MicroRNAs from Mouse , 2002, Current Biology.

[27]  Phillip D Zamore,et al.  Sequence-Specific Inhibition of Small RNA Function , 2004, PLoS biology.

[28]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[29]  M. Holmgren,et al.  Science on the Rise in Developing Countries , 2004, PLoS biology.

[30]  V. Ambros,et al.  The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. , 1999, Developmental biology.

[31]  L. Excoffier,et al.  Modern Humans Did Not Admix with Neanderthals during Their Range Expansion into Europe , 2004, PLoS biology.

[32]  A. Kuroiwa,et al.  Hoxa‐11 and Hoxa‐13 are involved in repression of MyoD during limb muscle development , 2003, Development, growth & differentiation.