Musashi1 Cooperates in Abnormal Cell Lineage Protein 28 (Lin28)-mediated Let-7 Family MicroRNA Biogenesis in Early Neural Differentiation*♦

Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural stem/progenitor cells (NS/PCs) as well as in other tissue stem cells. Msi1 binds to the 3′-UTR of its target mRNAs in NS/PCs, prevents their translation, and interferes with NS/PC differentiation. We previously showed that Msi1 competes with eIF4G to bind poly(A)-binding protein and inhibits assembly of the 80 S ribosome. Here we show that Msi1 works in concert with Lin28 to regulate post-transcriptional microRNA (miRNA) biogenesis in the cropping step, which occurs in the nucleus. Lin28 and its binding partner terminal uridylyltransferase 4 (TUT4) are known to maintain embryonic stem cell pluripotency by blocking let-7 miRNA biogenesis at the dicing step. Interestingly, we found that during early neural differentiation of embryonic stem cells, Msi1 enhanced the localization of Lin28 to the nucleus and also inhibited the nuclear cropping step of another let-7 family miRNA, miR98. These results suggest that Msi1 can influence stem cell maintenance and differentiation by controlling the subcellular localization of proteins involved in miRNA biogenesis, as well as by regulating the translation of its target mRNA.

[1]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[2]  V. Ambros,et al.  The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA , 1997, Cell.

[3]  Hisato Kondoh,et al.  Triggering neural differentiation of ES cells by subtype switching of importin-α , 2007, Nature Cell Biology.

[4]  M. Siomi,et al.  Posttranscriptional regulation of microRNA biogenesis in animals. , 2010, Molecular cell.

[5]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[6]  S. Balasubramanian,et al.  LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans , 2009, Nature Structural &Molecular Biology.

[7]  K. Mikoshiba,et al.  The Neural RNA-Binding Protein Musashi1 Translationally Regulates Mammalian numb Gene Expression by Interacting with Its mRNA , 2001, Molecular and Cellular Biology.

[8]  D. Chelsky,et al.  Sequence requirements for synthetic peptide-mediated translocation to the nucleus , 1989, Molecular and cellular biology.

[9]  Dong-Hua Yang,et al.  Temporally regulated expression of Lin-28 in diverse tissues of the developing mouse. , 2003, Gene expression patterns : GEP.

[10]  Hideyuki Okano,et al.  Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival , 2010, Molecular Cancer.

[11]  S. Minoshima,et al.  Nucleolar localization of DGCR8 and identification of eleven DGCR8-associated proteins. , 2007, Experimental cell research.

[12]  H. Okano,et al.  Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP , 2008, The Journal of cell biology.

[13]  H. Okano,et al.  Musashi1: An Evolutionally Conserved Marker for CNS Progenitor Cells Including Neural Stem Cells , 2000, Developmental Neuroscience.

[14]  C. Joo,et al.  TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation , 2009, Cell.

[15]  H. Okano,et al.  Expression of the neural RNA‐binding protein Musashi1 in human gliomas , 2001, Glia.

[16]  L. Smirnova,et al.  A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment , 2008, Nature Cell Biology.

[17]  H. Okano,et al.  Function of RNA-binding protein Musashi-1 in stem cells. , 2005, Experimental cell research.

[18]  John T. Powers,et al.  Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies , 2009, Nature Genetics.

[19]  J. M. Thomson,et al.  Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. , 2008, RNA.

[20]  G. Daley,et al.  Lin28: A MicroRNA Regulator with a Macro Role , 2010, Cell.

[21]  E. Moss,et al.  Localization of the Developmental Timing Regulator Lin28 to mRNP Complexes, P-bodies and Stress Granules , 2007, RNA biology.

[22]  C. Joo,et al.  Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. , 2008, Molecular cell.

[23]  R. Gregory,et al.  Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in embryonic stem cells , 2009, Nature Structural &Molecular Biology.

[24]  T. Shimazaki,et al.  Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells. , 2004, Developmental biology.

[25]  A. Harel-Bellan,et al.  Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. , 2007, Genes & development.

[26]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[27]  S. Hammond,et al.  Emerging paradigms of regulated microRNA processing. , 2010, Genes & development.

[28]  H. Okano,et al.  RNA-binding protein Musashi family: Roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Koizumi,et al.  Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell‐Derived Neural Stem/Progenitor Cells , 2008, Stem cells.

[30]  V. Kim,et al.  In vitro and in vivo assays for the activity of Drosha complex. , 2007, Methods in enzymology.

[31]  G. Daley,et al.  Selective Blockade of MicroRNA Processing by Lin28 , 2008, Science.

[32]  Piotr Sliz,et al.  Determinants of MicroRNA Processing Inhibition by the Developmentally Regulated RNA-binding Protein Lin28* , 2008, Journal of Biological Chemistry.

[33]  J. Cáceres,et al.  Antagonistic role of hnRNP A1 and KSRP in the regulation of Let-7a biogenesis , 2010, Nature Structural &Molecular Biology.

[34]  V. Kim,et al.  Biogenesis of small RNAs in animals , 2009, Nature Reviews Molecular Cell Biology.

[35]  K. Mikoshiba,et al.  Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. , 1996, Developmental biology.

[36]  H. Okano,et al.  Musashi: a translational regulator of cell fate. , 2002, Journal of cell science.

[37]  H. Okano,et al.  Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. , 2001, Differentiation; research in biological diversity.

[38]  D. Bartel,et al.  MicroRNAs in the Hox network: an apparent link to posterior prevalence , 2008, Nature Reviews Genetics.

[39]  V. Kim,et al.  Regulating the Regulators: Posttranslational Modifications of RNA Silencing Factors , 2009, Cell.

[40]  B. O’Malley,et al.  Maturation of microRNA is hormonally regulated by a nuclear receptor. , 2009, Molecular cell.

[41]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[42]  Q. Jiang,et al.  LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro , 2010, Development.

[43]  H. Okano,et al.  RNA-Binding Protein Musashi2: Developmentally Regulated Expression in Neural Precursor Cells and Subpopulations of Neurons in Mammalian CNS , 2001, The Journal of Neuroscience.