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Multiple In Vivo Biological Processes Are Mediated by Functionally Redundant Activities of and


Amongst the small number of miRNA knockouts that exhibit substantially overt phenotypes, mutants of Drosophila mir-279 are notable. Previous studies have uncovered its essential requirements in a range of developmental and behavioral assays. Surprisingly, we find that the phenotypes attributed to mir-279 deletions depend on the unanticipated loss of expression of the downstream locus mir-996, whose genomic locus is retained in extant mir-279 mutants. These miRNAs share their seed regions but are divergent elsewhere in the mature sequences. We use precise genetic engineering to show that a single endogenous copy of either mir-279 or mir-996 can fully rescue viability, olfactory neuron, and circadian rhythm defects of double deletion animals. These data and genetic reagents set a new foundation for developmental and behavioral studies of this critical miRNA locus. More generally, these data demonstrate that multiple loss-of-function phenotypes can be rescued by endogenous expression of divergent seed family members, highlighting the importance and potentially sufficiency of this region for in vivo function.


Vyšlo v časopise: Multiple In Vivo Biological Processes Are Mediated by Functionally Redundant Activities of and. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005245
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005245

Souhrn

Amongst the small number of miRNA knockouts that exhibit substantially overt phenotypes, mutants of Drosophila mir-279 are notable. Previous studies have uncovered its essential requirements in a range of developmental and behavioral assays. Surprisingly, we find that the phenotypes attributed to mir-279 deletions depend on the unanticipated loss of expression of the downstream locus mir-996, whose genomic locus is retained in extant mir-279 mutants. These miRNAs share their seed regions but are divergent elsewhere in the mature sequences. We use precise genetic engineering to show that a single endogenous copy of either mir-279 or mir-996 can fully rescue viability, olfactory neuron, and circadian rhythm defects of double deletion animals. These data and genetic reagents set a new foundation for developmental and behavioral studies of this critical miRNA locus. More generally, these data demonstrate that multiple loss-of-function phenotypes can be rescued by endogenous expression of divergent seed family members, highlighting the importance and potentially sufficiency of this region for in vivo function.


Zdroje

1. Yang JS, Lai EC (2011) Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular cell 43: 892–903. doi: 10.1016/j.molcel.2011.07.024 21925378

2. Kozomara A, Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic acids research 39: D152–157. doi: 10.1093/nar/gkq1027 21037258

3. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233. doi: 10.1016/j.cell.2009.01.002 19167326

4. Sun K, Lai EC (2013) Adult-specific functions of animal microRNAs. Nature reviews Genetics 14: 535–548. doi: 10.1038/nrg3471 23817310

5. Mendell JT, Olson EN (2012) MicroRNAs in stress signaling and human disease. Cell 148: 1172–1187. doi: 10.1016/j.cell.2012.02.005 22424228

6. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843–854. 8252621

7. Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75: 855–862. 8252622

8. Reinhart BJ, Slack F, Basson M, Pasquinelli A, Bettinger J, et al. (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403: 901–906. 10706289

9. Lai EC (2002) microRNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation. Nature genetics 30: 363–364. 11896390

10. Lai EC, Burks C, Posakony JW (1998) The K box, a conserved 3' UTR sequence motif, negatively regulates accumulation of Enhancer of split Complex transcripts. Development 125: 4077–4088. 9735368

11. Lai EC, Posakony JW (1997) The Bearded box, a novel 3' UTR sequence motif, mediates negative post-transcriptional regulation of Bearded and Enhancer of split Complex gene expression. Development 124: 4847–4856. 9428421

12. Miska EA, Alvarez-Saavedra E, Abbott AL, Lau NC, Hellman AB, et al. (2007) Most Caenorhabditis elegans microRNAs Are Individually Not Essential for Development or Viability. PLoS genetics 3: e215. 18085825

13. Smibert P, Lai EC (2008) Lessons from microRNA mutants in worms, flies and mice. Cell cycle 7: 2500–2508. 18719388

14. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, et al. (2008) The impact of microRNAs on protein output. Nature 455: 64–71. doi: 10.1038/nature07242 18668037

15. Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58–63. doi: 10.1038/nature07228 18668040

16. Ebert MS, Sharp PA (2012) Roles for microRNAs in conferring robustness to biological processes. Cell 149: 515–524. doi: 10.1016/j.cell.2012.04.005 22541426

17. Lai EC, Tomancak P, Williams RW, Rubin GM (2003) Computational identification of Drosophila microRNA genes. Genome biology 4: R42.41–R42.20.

18. Cayirlioglu P, Kadow IG, Zhan X, Okamura K, Suh GS, et al. (2008) Hybrid neurons in a microRNA mutant are putative evolutionary intermediates in insect CO2 sensory systems. Science 319: 1256–1260. doi: 10.1126/science.1149483 18309086

19. Chalfie M, Horvitz HR, Sulston JE (1981) Mutations that lead to reiterations in the cell lineages of C. elegans. Cell 24: 59–69. 7237544

20. Johnston RJ, Hobert O (2003) A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426: 845–849. 14685240

21. Lewis MA, Quint E, Glazier AM, Fuchs H, De Angelis MH, et al. (2009) An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nature genetics 41: 614–618. doi: 10.1038/ng.369 19363478

22. Mencia A, Modamio-Hoybjor S, Redshaw N, Morin M, Mayo-Merino F, et al. (2009) Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nature genetics 41: 609–613. doi: 10.1038/ng.355 19363479

23. Hartl M, Loschek LF, Stephan D, Siju KP, Knappmeyer C, et al. (2011) A New Prospero and microRNA-279 Pathway Restricts CO2 Receptor Neuron Formation. The Journal of neuroscience: the official journal of the Society for Neuroscience 31: 15660–15673. doi: 10.1523/JNEUROSCI.2592-11.2011 22049409

24. Luo W, Sehgal A (2012) Regulation of Circadian Behavioral Output via a MicroRNA-JAK/STAT Circuit. Cell 148: 765–779. doi: 10.1016/j.cell.2011.12.024 22305007

25. Yoon WH, Meinhardt H, Montell DJ (2011) miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold. Nature cell biology 13: 1062–1069. doi: 10.1038/ncb2316 21857668

26. Ruby JG, Stark A, Johnston WK, Kellis M, Bartel DP, et al. (2007) Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome research 17: 1850–1864. 17989254

27. Stark A, Kheradpour P, Parts L, Brennecke J, Hodges E, et al. (2007) Systematic discovery and characterization of fly microRNAs using 12 Drosophila genomes. Genome research 17: 1865–1879. 17989255

28. Mohammed J, Siepel A, Lai EC (2014) Diverse modes of evolutionary emergence and flux of conserved microRNA clusters. RNA in press.

29. Bushati N, Stark A, Brennecke J, Cohen SM (2008) Temporal Reciprocity of miRNAs and Their Targets during the Maternal-to-Zygotic Transition in Drosophila. Curr Biol 18: 501–506. doi: 10.1016/j.cub.2008.02.081 18394895

30. Aboobaker AA, Tomancak P, Patel N, Rubin GM, Lai EC (2005) Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proceedings of the National Academy of Sciences of the United States of America 102: 18017–18022. 16330759

31. Wen J, Mohammed J, Bortolamiol-Becet D, Tsai H, Robine N, et al. (2014) Diversity of miRNAs, siRNAs and piRNAs across 25 Drosophila cell lines. Genome research 24: 1236–1250. doi: 10.1101/gr.161554.113 24985917

32. Brown JB, Boley N, Eisman R, May G, Stoiber M, et al. (2014) Diversity and dynamics of the Drosophila transcriptome. Nature 512: 393–399. 24670639

33. Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, et al. (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471: 473–479. doi: 10.1038/nature09715 21179090

34. Manak JR, Dike S, Sementchenko V, Kapranov P, Biemar F, et al. (2006) Biological function of unannotated transcription during the early development of Drosophila melanogaster. Nature genetics 38: 1151–1158. 16951679

35. Linsley PS, Schelter J, Burchard J, Kibukawa M, Martin MM, et al. (2007) Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Molecular and cellular biology 27: 2240–2252. 17242205

36. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, et al. (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769–773. 15685193

37. Lai EC (2015) Two decades of miRNA biology: lessons and challenges. RNA 21: 675–677. doi: 10.1261/rna.051193.115 25780186

38. Chen YW, Song S, Weng R, Verma P, Kugler JM, et al. (2014) Systematic Study of Drosophila MicroRNA Functions Using a Collection of Targeted Knockout Mutations. Developmental cell 31: 784–800. doi: 10.1016/j.devcel.2014.11.029 25535920

39. Alvarez-Saavedra E, Horvitz HR (2010) Many families of C. elegans microRNAs are not essential for development or viability. Curr Biol 20: 367–373. doi: 10.1016/j.cub.2009.12.051 20096582

40. Abbott AL, Alvarez-Saavedra E, Miska EA, Lau NC, Bartel DP, et al. (2005) The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. Developmental cell 9: 403–414. 16139228

41. Brenner JL, Jasiewicz KL, Fahley AF, Kemp BJ, Abbott AL (2010) Loss of individual microRNAs causes mutant phenotypes in sensitized genetic backgrounds in C. elegans. Curr Biol 20: 1321–1325. doi: 10.1016/j.cub.2010.05.062 20579881

42. Smibert P, Lai EC (2010) A view from Drosophila: multiple biological functions for individual microRNAs. Seminars in cell & developmental biology 21: 745–753.

43. Small EM, Olson EN (2011) Pervasive roles of microRNAs in cardiovascular biology. Nature 469: 336–342. doi: 10.1038/nature09783 21248840

44. Li X, Cassidy JJ, Reinke CA, Fischboeck S, Carthew RW (2009) A microRNA imparts robustness against environmental fluctuation during development. Cell 137: 273–282. doi: 10.1016/j.cell.2009.01.058 19379693

45. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294: 853–858. 11679670

46. Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes & development 18: 504–511.

47. Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of MicroRNA-Target Recognition. PLoS biology 3: e85. 15723116

48. Lai EC, Tam B, Rubin GM (2005) Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs. Genes & development 19: 1067–1080.

49. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115: 787–798. 14697198

50. Stark A, Brennecke J, Russell RB, Cohen SM (2003) Identification of Drosophila MicroRNA Targets. PLoS biology 1: E60. 14691535

51. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, et al. (2005) Combinatorial microRNA target predictions. Nature genetics 37: 495–500. 15806104

52. Vella MC, Choi EY, Lin SY, Reinert K, Slack FJ (2004) The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3'UTR. Genes & development 18: 132–137.

53. Lal A, Navarro F, Maher CA, Maliszewski LE, Yan N, et al. (2009) miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. Molecular cell 35: 610–625. doi: 10.1016/j.molcel.2009.08.020 19748357

54. Shin C, Nam JW, Farh KK, Chiang HR, Shkumatava A, et al. (2010) Expanding the MicroRNA Targeting Code: Functional Sites with Centered Pairing. Molecular cell 38: 789–802. doi: 10.1016/j.molcel.2010.06.005 20620952

55. Sarin S, O'Meara MM, Flowers EB, Antonio C, Poole RJ, et al. (2007) Genetic screens for Caenorhabditis elegans mutants defective in left/right asymmetric neuronal fate specification. Genetics 176: 2109–2130. 17717195

56. Nairz K, Rottig C, Rintelen F, Zdobnov E, Moser M, et al. (2006) Overgrowth caused by misexpression of a microRNA with dispensable wild-type function. Developmental biology 291: 314–324. 16443211

57. Bassett AR, Azzam G, Wheatley L, Tibbit C, Rajakumar T, et al. (2014) Understanding functional miRNA-target interactions in vivo by site-specific genome engineering. Nature communications 5: 4640. doi: 10.1038/ncomms5640 25135198

58. Ecsedi M, Rausch M, Grosshans H (2015) The let-7 microRNA Directs Vulval Development through a Single Target. Developmental cell 32: 335–344. doi: 10.1016/j.devcel.2014.12.018 25669883

59. Pfeiffer BD, Jenett A, Hammonds AS, Ngo TT, Misra S, et al. (2008) Tools for neuroanatomy and neurogenetics in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 105: 9715–9720. doi: 10.1073/pnas.0803697105 18621688

60. Venken KJ, He Y, Hoskins RA, Bellen HJ (2006) P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314: 1747–1751. 17138868

61. Bejarano F, Bortolamiol-Becet D, Dai Q, Sun K, Saj A, et al. (2012) A genome-wide transgenic resource for conditional expression of Drosophila microRNAs. Development 139: 2821–2831. doi: 10.1242/dev.079939 22745315

62. Blau J, Young MW (1999) Cycling vrille expression is required for a functional Drosophila clock. Cell 99: 661–671. 10612401

63. Jones WD, Cayirlioglu P, Kadow IG, Vosshall LB (2007) Two chemosensory receptors together mediate carbon dioxide detection in Drosophila. Nature 445: 86–90. 17167414

64. Pfeiffenberger C, Lear BC, Keegan KP, Allada R (2010) Processing circadian data collected from the Drosophila Activity Monitoring (DAM) System. Cold Spring Harbor protocols 2010: pdb prot5519. doi: 10.1101/pdb.prot5519 21041392

65. Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130: 89–100. 17599402

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