Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development

English version

Autoři: Angelina Zheleva ^aff001; Eva Gómez-Orte ^aff001; Beatriz Sáenz-Narciso ^aff001; Begoña Ezcurra ^aff001; Henok Kassahun ^aff002; María de Toro ^aff001; Antonio Miranda-Vizuete ^aff004; Ralf Schnabel ^aff005; Hilde Nilsen ^aff002; Juan Cabello ^aff001
Působiště autorů: CIBIR (Center for Biomedical Research of La Rioja), Logroño, La Rioja, Spain ^aff001; Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, Lørenskog, Norway ^aff002; South-Eastern Norway Regional Health Authority, Hamar, Norway ^aff003; Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ^aff004; Institute of Genetics, Technische Universität Braunschweig, Germany ^aff005
Vyšlo v časopise: Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008338
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008338

Souhrn

Animal development requires the execution of specific transcriptional programs in different sets of cells to build tissues and functional organs. Transcripts are exported from the nucleus to the cytoplasm where they are translated into proteins that, ultimately, carry out the cellular functions. Here we show that in Caenorhabditis elegans, reduction of mRNA export strongly affects epithelial morphogenesis and germline proliferation while other tissues remain relatively unaffected. Epithelialization and gamete formation demand a large number of transcripts in the cytoplasm for the duration of these processes. In addition, our findings highlight the existence of a regulatory feedback mechanism that activates gene expression in response to low levels of cytoplasmic mRNA. We expand the genetic characterization of nuclear export factor NXF-1 to other members of the mRNA export pathway to model mRNA export and recycling of NXF-1 back to the nucleus. Our model explains how mutations in genes involved in general processes, such as mRNA export, may result in tissue-specific developmental phenotypes.

Klíčová slova:

Biology and life sciences – Developmental biology – Embryology – Embryos – Organisms – Eukaryota – Animals – Invertebrates – Nematoda – Caenorhabditis – Caenorhabditis elegans – Genetics – Epigenetics – RNA interference – Gene expression – Genetic interference – Biochemistry – Nucleic acids – RNA – Messenger RNA – Cell biology – Cellular structures and organelles – Cytoplasm – Cell processes – Cell cycle and cell division – Anatomy – Digestive system – Pharynx – Respiratory system – Reproductive system – Genital anatomy – Gonads – Research and analysis methods – Animal studies – Experimental organism systems – Model organisms – Animal models – Medicine and health sciences

Zdroje

1. Culjkovic-Kraljacic B and Borden KL. Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol. 2013; 23: 328–335. doi: 10.1016/j.tcb.2013.03.004 23582887

2. Katahira J. Nuclear export of messenger RNA. Genes (Basel). 2015; 6: 163–184.

3. Delaleau M and Borden KL. Multiple Export Mechanisms for mRNAs. Cells. 2015; 4: 452–473. doi: 10.3390/cells4030452 26343730

4. Sloan KE, Gleizes PE and Bohnsack MT. Nucleocytoplasmic Transport of RNAs and RNA–Protein Complexes. J Mol Biol. 2016; 428: 2040–2059. doi: 10.1016/j.jmb.2015.09.023 26434509

5. Bjork P and Wieslander L. Integration of mRNP formation and export. Cell Mol Life Sci. 2017; 74: 2875–2897. doi: 10.1007/s00018-017-2503-3 28314893

6. Izaurralde E. Friedrich Miescher Prize awardee lecture review. A conserved family of nuclear export receptors mediates the exit of messenger RNA to the cytoplasm. Cell Mol Life Sci. 2001; 58: 1105–1112. doi: 10.1007/PL00000924 11529502

7. Adam SA. The nuclear transport machinery in Caenorhabditis elegans: A central role in morphogenesis. Semin Cell Dev Biol. 2009; 20: 576–581. doi: 10.1016/j.semcdb.2009.03.013 19577735

8. Bonnet A and Palancade B. Regulation of mRNA trafficking by nuclear pore complexes. Genes (Basel). 2014; 5: 767–791.

9. Piruat JI and Aguilera A. A novel yeast gene, THO2, is involved in RNA pol II transcription and provides new evidence for transcriptional elongation-associated recombination. EMBO J. 1998; 17:4859–4872 doi: 10.1093/emboj/17.16.4859 9707445

10. Castellano-Pozo M, Garcia-Muse T, Aguilera A. The Caenorhabditis elegans THO Complex Is Required for the Mitotic Cell Cycle and Development. PLoS ONE. 2012; 7(12): e52447. doi: 10.1371/journal.pone.0052447 23285047

11. Kurshakova MM, Georgieva SG and Kopytova DV. Protein complexes coordinating mRNA export from the nucleus into the cytoplasm. Mol Biol (Mosk). 2016; 50: 723–729.

12. Rondon AG, Jimeno S and Aguilera A. The interface between transcription and mRNP export: from THO to THSC/TREX-2. Biochim Biophys Acta. 2010; 1799: 533–538. doi: 10.1016/j.bbagrm.2010.06.002 20601280

13. Luna R, Rondón AG and Aguilera A. New clues to understand the role of THO and other functionally related factors in mRNP biogenesis. Biochimica et Biophysica Acta (BBA)—Gene Regulatory Mechanisms. 2012; 1819: 514–520.

14. Pena A, Gewartowski K, Mroczek S, Cuellar J, Szykowska A, Prokop A, Czarnocki-Cieciura M, Piwowarski J, Tous C, Aguilera A. et al. Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor. EMBO J. 2012; 31: 1605–1616. doi: 10.1038/emboj.2012.10 22314234

15. Heath CG, Viphakone N and Wilson SA. The role of TREX in gene expression and disease. Biochem J. 2016; 473: 2911–2935. doi: 10.1042/BCJ20160010 27679854

16. Viphakone N, Hautbergue GM, Walsh M, Chang CT, Holland A, Folco EG, Reed R and Wilson SA. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun. 2012; 3: 1006. doi: 10.1038/ncomms2005 22893130

17. Walsh MJ, Hautbergue GM and Wilson SA. Structure and function of mRNA export adaptors. Biochem Soc Trans. 2010; 38: 232–236. doi: 10.1042/BST0380232 20074066

18. Braun IC, Herold A, Rode M, Conti E and Izaurralde E. Overexpression of TAP/p15 heterodimers bypasses nuclear retention and stimulates nuclear mRNA export. J Biol Chem. 2001; 276: 20536–20543. doi: 10.1074/jbc.M100400200 11259411

19. Santos-Rosa H, Moreno H, Simos G, Segref A, Fahrenkrog B, Pante N. and Hurt E. Nuclear mRNA export requires complex formation between Mex67p and Mtr2p at the nuclear pores. Mol Cell Biol. 1998; 18: 6826–6838. doi: 10.1128/mcb.18.11.6826 9774696

20. Herold A, Suyama M, Rodrigues JP, Braun IC, Kutay U, Carmo-Fonseca M, Bork P and Izaurralde E. TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture. Mol Cell Biol. 2000; 20: 8996–9008. doi: 10.1128/mcb.20.23.8996-9008.2000 11073998

21. Suyama M, Doerks T, Braun IC, Sattler M, Izaurralde E and Bork P. Prediction of structural domains of TAP reveals details of its interaction with p15 and nucleoporins. EMBO Rep. 2000; 1: 53–58. doi: 10.1093/embo-reports/kvd009 11256625

22. Senay C, Ferrari P, Rocher C, Rieger KJ, Winter J, Platel D and Bourne Y. The Mtr2-Mex67 NTF2-like domain complex. Structural insights into a dual role of Mtr2 for yeast nuclear export. J Biol Chem. 2003; 278: 48395–48403. doi: 10.1074/jbc.M308275200 14504280

23. Bachi A, Braun IC, Rodrigues JP, Pante N, Ribbeck K, von Kobbe C, Kutay U, Wilm M, Gorlich D, Carmo-Fonseca M et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates. RNA. 2000; 6: 136–158. doi: 10.1017/s1355838200991994 10668806

24. Strasser K, Bassler J and Hurt E. Binding of the Mex67p/Mtr2p heterodimer to FXFG, GLFG, and FG repeat nucleoporins is essential for nuclear mRNA export. J Cell Biol. 2000; 150: 695–706. doi: 10.1083/jcb.150.4.695 10952996

25. Fribourg S, Braun IC, Izaurralde E and Conti E. Structural Basis for the Recognition of a Nucleoporin FG Repeat by the NTF2-like Domain of the TAP/p15 mRNA Nuclear Export Factor. Mol Cell. 2001; 8: 645–656. 11583626

26. Saffman EE and Lasko P. Germline development in vertebrates and invertebrates. Cell Mol Life Sci. 1999; 55: 1141–1163. 10442094

27. Strome S. Specification of the germ line. WormBook. 2005; 1–10.

28. Sheth U, Pitt J, Dennis S and Priess JR. Perinuclear P granules are the principal sites of mRNA export in adult C. elegans germ cells. Development. 2010; 137: 1305–1314. doi: 10.1242/dev.044255 20223759

29. Quintin S, Michaux G, McMahon L, Gansmuller A and Labouesse M. The Caenorhabditis elegans Gene lin-26 Can Trigger Epithelial Differentiation without Conferring Tissue Specificity. Dev Biol. 2001; 235: 410–421. doi: 10.1006/dbio.2001.0294 11437447

30. White J. The anatomy, The nematode Caenorhabditis elegans. Cold Spring Harbor Laboratory Press. 1988; 81–122.

31. Albertson DG and Thomson JN. The pharynx of Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci. 1976; 275: 299–325. doi: 10.1098/rstb.1976.0085 8805

32. Portereiko MF and Mango SE. Early morphogenesis of the Caenorhabditis elegans pharynx. Dev Biol. 2001; 233: 482–494. doi: 10.1006/dbio.2001.0235 11336509

33. Portereiko MF, Saam J and Mango SE. ZEN-4/MKLP1 is required to polarize the foregut epithelium. Curr Biol. 2004; 14: 932–941. doi: 10.1016/j.cub.2004.05.052 15182666

34. Knust E and Bossinger O. Composition and formation of intercellular junctions in epithelial cells. Science. 2002; 298: 1955–1959. doi: 10.1126/science.1072161 12471248

35. Von Stetina SE and Mango SE. PAR-6, but not E-cadherin and beta-integrin, is necessary for epithelial polarization in C. elegans. Dev Biol. 2015; 403: 5–14. doi: 10.1016/j.ydbio.2015.03.002 25773364

36. Von Stetina SE, Liang J, Marnellos G and Mango SE. Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6. Mol Biol Cell. 2017; 28: 2042–2065. doi: 10.1091/mbc.E16-09-0644 28539408

37. Costa M, Raich W, Agbunag C, Leung B, Hardin J and Priess JR. A putative catenin-cadherin system mediates morphogenesis of the Caenorhabditis elegans embryo. J Cell Biol. 1998; 141: 297–308. doi: 10.1083/jcb.141.1.297 9531567

38. Simske JS, Koppen M, Sims P, Hodgkin J, Yonkof A and Hardin J. The cell junction protein VAB-9 regulates adhesion and epidermal morphology in C. elegans. Nat Cell Biol. 2003; 5: 619–625. doi: 10.1038/ncb1002 12819787

39. Bossinger O, Klebes A, Segbert C, Theres C and Knust E. Zonula adherens formation in Caenorhabditis elegans requires dlg-1, the homologue of the Drosophila gene discs large. Dev Biol. 2001; 230: 29–42. doi: 10.1006/dbio.2000.0113 11161560

40. Koppen M, Simske JS, Sims PA, Firestein BL, Hall DH, Radice AD, Rongo C and Hardin JD. Cooperative regulation of AJM-1 controls junctional integrity in Caenorhabditis elegans epithelia. Nat Cell Biol. 2001; 3: 983–991. doi: 10.1038/ncb1101-983 11715019

41. Tan W, Zolotukhin AS, Bear J, Patenaude DJ and Felber BK. The mRNA export in Caenorhabditis elegans is mediated by Ce-NXF-1, an ortholog of human TAP/NXF and Saccharomyces cerevisiae Mex67p. RNA. 2000; 6: 1762–1772. doi: 10.1017/s1355838200000832 11142376

42. Minevich G, Park DS, Blankenberg D, Poole RJ. and Hobert O. CloudMap: a cloud-based pipeline for analysis of mutant genome sequences. Genetics. 2012; 192: 1249–1269. doi: 10.1534/genetics.112.144204 23051646

43. Gordon CL, King J. Genetic properties of temperature-sensitive folding mutants of the coat protein of phage P22. Genetics. 1994; 136:427–438 8150274

44. Okkema PG, Harrison SW, Plunger V, Aryana A and Fire A. Sequence requirements for myosin gene expression and regulation in Caenorhabditis elegans. Genetics. 1993; 135: 385–404. 8244003

45. Morck C, Axang C and Pilon M. A genetic analysis of axon guidance in the C elegans pharynx. Dev Biol. 2003; 260: 158–175. doi: 10.1016/s0012-1606(03)00238-0 12885562

46. Mango SE, Lambie EJ and Kimble J. The pha-4 gene is required to generate the pharyngeal primordium of Caenorhabditis elegans. Development. 1994; 120: 3019–3031. 7607089

47. Kalb JM, Lau KK, Goszczynski B, Fukushige T, Moons D, Okkema PG and McGhee JD. pha-4 is Ce-fkh-1, a fork head/HNF-3alpha,beta,gamma homolog that functions in organogenesis of the C. elegans pharynx. Development. 1998; 125: 2171–2180. 9584117

48. Gaudet J and Mango SE. Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4. Science. 2002; 295: 821–825. doi: 10.1126/science.1065175 11823633

49. Gaudet J, Muttumu S, Horner M and Mango SE. Whole-Genome Analysis of Temporal Gene Expression during Foregut Development. PLoS Biol. 2004; 2(11): e352. doi: 10.1371/journal.pbio.0020352 15492775

50. Kuchenthal CA, Chen W and Okkema PG. Multiple enhancers contribute to expression of the NK-2 homeobox gene ceh-22 in C. elegans pharyngeal muscle. Genesis. 2001; 31: 156–166. 11783006

51. Smith PA and Mango SE. Role of T-box gene tbx-2 for anterior foregut muscle development in C. elegans. Dev Biol. 2007; 302: 25–39. doi: 10.1016/j.ydbio.2006.08.023 17005176

52. Vilimas T, Abraham A and Okkema PG. An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22 gene is targeted by the Forkhead factor PHA-4. Dev Biol. 2004; 266: 388–398. doi: 10.1016/j.ydbio.2003.10.015 14738885

53. Mango SE. The C. elegans pharynx: a model for organogenesis. WormBook. 2007; 1–26.

54. Mango SE. The molecular basis of organ formation: insights from the C. elegans foregut. Annu Rev Cell Dev Biol. 2009; 25: 597–628. doi: 10.1146/annurev.cellbio.24.110707.175411 19575642

55. Pettitt J, Wood WB and Plasterk RH. cdh-3, a gene encoding a member of the cadherin superfamily, functions in epithelial cell morphogenesis in Caenorhabditis elegans. Development. 1996; 122: 4149–4157. 9012534

56. Zipkin ID, Kindt RM and Kenyon CJ. Role of a new Rho family member in cell migration and axon guidance in C. elegans. Cell. 1997; 90: 883–894. doi: 10.1016/s0092-8674(00)80353-0 9298900

57. Chen L, Ong B and Bennett V. LAD-1, the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signaling. J Cell Biol. 2001; 154: 841–855. doi: 10.1083/jcb.200009004 11502758

58. Kerkow DE, Carmel AB, Menichelli E, Ambrus G, Hills RD Jr, Gerace L and Williamson JR. The structure of the NXF2/NXT1 heterodimeric complex reveals the combined specificity and versatility of the NTF2-like fold. J Mol Biol. 2012; 415: 649–665. doi: 10.1016/j.jmb.2011.11.027 22123199

59. Longman D, Johnstone IL and Caceres JF. The Ref/Aly proteins are dispensable for mRNA export and development in Caenorhabditis elegans. RNA. 2003; 9: 881–891. doi: 10.1261/rna.5420503 12810921

60. MacMorris M, Brocker C and Blumenthal T. UAP56 levels affect viability and mRNA export in Caenorhabditis elegans. RNA. 2003; 9: 847–857. doi: 10.1261/rna.5480803 12810918

61. Liu Z, Fujii T, Nukazuka A, Kurokawa R, Suzuki M, Fujisawa H and Takagi S. C. elegans PlexinA PLX-1 mediates a cell contact-dependent stop signal in vulval precursor cells. Dev Biol. 2005; 282: 138–151. doi: 10.1016/j.ydbio.2005.03.002 15936335

62. Shiimori M, Inoue K and Sakamoto H. A specific set of exon junction complex subunits is required for the nuclear retention of unspliced RNAs in Caenorhabditis elegans. Mol Cell Biol. 2013; 33: 444–456. doi: 10.1128/MCB.01298-12 23149939

63. Hir HL, Sauliere J and Wang Z. The exon junction complex as a node of post-transcriptional networks. Nat Rev Mol Cell Biol. 2016; 17: 41–54. doi: 10.1038/nrm.2015.7 26670016

64. Boehm V and Gehring NH. Exon Junction Complexes: Supervising the Gene Expression Assembly Line. Trends Genet. 2016; 32: 724–735. doi: 10.1016/j.tig.2016.09.003 27667727

65. Woodward LA, Mabin JW, Gangras P and Singh G. The exon junction complex: a lifelong guardian of mRNA fate. Wiley Interdiscip Rev RNA. 2017; 8(3).

66. Kawano T, Kataoka N, Dreyfuss G and Sakamoto H. Ce-Y14 and MAG-1, components of the exon-exon junction complex, are required for embryogenesis and germline sexual switching in Caenorhabditis elegans. Mech Dev. 2004; 121: 27–35. doi: 10.1016/j.mod.2003.11.003 14706697

67. Evans TC and Hunter CP. Translational control of maternal RNAs. WormBook. 2005; 1–11.

68. Robertson S and Lin R. The Maternal-to-Zygotic Transition in C. elegans. Curr Top Dev Biol. 2015; 113: 1–42. doi: 10.1016/bs.ctdb.2015.06.001 26358869

69. Vought VE, Ohmachi M, Lee MH, Maine EM. EGO-1, a putative RNA-directed RNA polymerase, promotes germline proliferation in parallel with GLP-1/notch signaling and regulates the spatial organization of nuclear pore complexes and germline P granules in Caenorhabditis elegans. Genetics 2005;170(3):1121–32. Epub 2005 May 23 doi: 10.1534/genetics.105.042135 15911573

70. Pepper AS, Lo TW, Killian DJ, Hall DH, Hubbard EJ. The establishment of Caenorhabditis elegans germline pattern is controlled by overlapping proximal and distal somatic gonad signals. Dev Biol. 2003; 259(2):336–50 doi: 10.1016/s0012-1606(03)00203-3 12871705

71. Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP and Allis CD. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997; 106: 348–360. doi: 10.1007/s004120050256 9362543

72. Moser SC, von Elsner S, Bussing I, Alpi A, Schnabel R and Gartner A. Functional dissection of Caenorhabditis elegans CLK-2/TEL2 cell cycle defects during embryogenesis and germline development. PLoS Genet. 2009; 5(4): e1000451. doi: 10.1371/journal.pgen.1000451 19360121

73. Bailly AP, Freeman A, Hall J, Declais AC, Alpi A, Lilley DM, Ahmed S and Gartner A. The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair. PLoS Genet. 2010; 6(7): e1001025. doi: 10.1371/journal.pgen.1001025 20661466

74. Alpi A, Pasierbek P, Gartner A and Loidl J. Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans. Chromosoma. 2003; 112: 6–16. doi: 10.1007/s00412-003-0237-5 12684824

75. Ward JD, Barber LJ, Petalcorin MI, Yanowitz J and Boulton SJ. Replication blocking lesions present a unique substrate for homologous recombination. EMBO J. 2007; 26: 3384–3396. doi: 10.1038/sj.emboj.7601766 17611606

76. Dernburg AF, McDonald K, Moulder G, Barstead R, Dresser M and Villeneuve AM. Meiotic recombination in C. elegans initiates by a conserved mechanism and is dispensable for homologous chromosome synapsis. Cell. 1998; 94: 387–398. doi: 10.1016/s0092-8674(00)81481-6 9708740

77. Yu G, Wang LG, Han Y and He QY. ClusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16: 284–287. doi: 10.1089/omi.2011.0118 22455463

78. Hastings MH, Maywood ES, O'Neill JS. Cellular circadian pacemaking and the role of cytosolic rhythms. Current Biology. 2008; 18 (17): R805–R815 doi: 10.1016/j.cub.2008.07.021 18786386

79. Sheredos B. Scientific Diagrams as Traces of Group-Dependent Cognition: A Brief Cognitive-Historical Analysis". Proceedings of the Annual Meeting of the Cognitive Science Society. 2013; 35 (35).

80. Andreani TS, Itoh TQ, Yildirim E, Hwangbo DS, Allada R. Genetics of Circadian Rhythms. Sleep Medicine Clinics 2015. 10 (4): 413–21 doi: 10.1016/j.jsmc.2015.08.007 26568119

81. Dunlap JC, Loros JJ, Colot HV, Mehra A, Belden WJ, Shi M, Hong CI, Larrondo LF, Baker CL, Chen CH, Schwerdtfeger C, Collopy PD, Gamsby JJ, Lambreghts R. A circadian clock in Neurospora: how genes and proteins cooperate to produce a sustained, entrainable, and compensated biological oscillator with a period of about a day". Cold Spring Harbor Symposia on Quantitative Biology. 2007; 72: 57–68 doi: 10.1101/sqb.2007.72.072 18522516

82. Sanchez SE, Kay SA. The Plant Circadian Clock: From a Simple Timekeeper to a Complex Developmental Manager. Cold Spring Harbor Perspectives in Biology. 2016; 8 (12): a027748 doi: 10.1101/cshperspect.a027748 27663772

83. Condeelis J and Singer RH. How and why does beta-actin mRNA target?. Biol Cell. 2005; 97: 97–110. doi: 10.1042/BC20040063 15601261

84. Regmi SG, Rolland SG and Conradt B. Age-dependent changes in mitochondrial morphology and volume are not predictors of lifespan. Aging (Albany NY). 2014; 6: 118–130.

85. Boldogh IR, Pon LA. Interactions of mitochondria with the actin cytoskeleton. Biochim Biophys Acta. 2006; 1763: 450–462 doi: 10.1016/j.bbamcr.2006.02.014 16624426

86. Chin-Sang ID and Chisholm AD. Form of the worm: genetics of epidermal morphogenesis in C. elegans. Trends Genet. 2000; 16: 544–551. 11102704

87. Saenz-Narciso B, Gomez-Orte E, Zheleva A, Gastaca I and Cabello J. Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated. Bioessays. 2016; 38: 1246–1254. doi: 10.1002/bies.201600165 27790724

88. Goldberg MW. Nuclear pore complex tethers to the cytoskeleton. Semin Cell Dev Biol. 2017; 68: 52–58. doi: 10.1016/j.semcdb.2017.06.017 28676424

89. Forler D, Rabut G, Ciccarelli FD, Herold A, Kocher T, Niggeweg R, Bork P, Ellenberg J and Izaurralde E. RanBP2/Nup358 provides a major binding site for NXF1-p15 dimers at the nuclear pore complex and functions in nuclear mRNA export. Mol Cell Biol. 2004; 24: 1155–1167. doi: 10.1128/MCB.24.3.1155-1167.2004 14729961

90. Cohen-Fix O and Askjaer P. Cell Biology of the Caenorhabditis elegans Nucleus. Genetics. 2017; 205: 25–59. doi: 10.1534/genetics.116.197160 28049702

91. Anderson P and Kedersha N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol. 2009; 10: 430–436. doi: 10.1038/nrm2694 19461665

92. Decker CJ and Parker R. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb Perspect Biol. 2012; 4(9): a012286. doi: 10.1101/cshperspect.a012286 22763747

93. Luo Y, Na Z and Slavoff SA. P-Bodies: Composition, Properties, and Functions. Biochemistry. 2018; 57: 2424–2431. doi: 10.1021/acs.biochem.7b01162 29381060

94. Boag PR, Nakamura A and Blackwell TK. A conserved RNA-protein complex component involved in physiological germline apoptosis regulation in C. elegans. Development. 2005; 132: 4975–4986. doi: 10.1242/dev.02060 16221731

95. Boag PR, Atalay A, Robida S, Reinke V and Blackwell TK. Protection of specific maternal messenger RNAs by the P body protein CGH-1 (Dhh1/RCK) during Caenorhabditis elegans oogenesis. J Cell Biol. 2008; 182: 543–557. doi: 10.1083/jcb.200801183 18695045

96. Audhya A, Hyndman F, McLeod IX, Maddox AS, Yates JR 3rd, Desai A and Oegema K. A complex containing the Sm protein CAR-1 and the RNA helicase CGH-1 is required for embryonic cytokinesis in Caenorhabditis elegans. J Cell Biol. 2005; 171: 267–279. doi: 10.1083/jcb.200506124 16247027

97. Kabat JL, Barberan-Soler S and Zahler AM. HRP-2, the Caenorhabditis elegans homolog of mammalian heterogeneous nuclear ribonucleoproteins Q and R, is an alternative splicing factor that binds to UCUAUC splicing regulatory elements. J Biol Chem. 2009; 284: 28490–28497. doi: 10.1074/jbc.M109.023101 19706616

98. Cautain B, Hill R, de Pedro N and Link W. Components and regulation of nuclear transport processes. FEBS J. 2015; 282: 445–462. doi: 10.1111/febs.13163 25429850

99. Shamsher MK, Ploski J and Radu A. Karyopherin beta 2B participates in mRNA export from the nucleus. Proc Natl Acad Sci U S A. 2002; 99: 14195–14199. doi: 10.1073/pnas.212518199 12384575

100. Horner MA, Quintin S, Domeier ME, Kimble J, Labouesse M and Mango SE. pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in Caenorhabditis elegans. Genes Dev. 1998; 12: 1947–1952. doi: 10.1101/gad.12.13.1947 9649499

101. Zaidel-Bar R, Joyce MJ, Lynch AM, Witte K, Audhya A and Hardin J. The F-BAR domain of SRGP-1 facilitates cell-cell adhesion during C. elegans morphogenesis. J Cell Biol. 2010; 191: 761–769. doi: 10.1083/jcb.201005082 21059849

102. Raich WB, Agbunag C and Hardin J. Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Current Biology. 1999; 9: 1139–1146. doi: 10.1016/S0960-9822(00)80015-9 10531027

103. Achilleos A, Wehman AM and Nance J. PAR-3 mediates the initial clustering and apical localization of junction and polarity proteins during C. elegans intestinal epithelial cell polarization. Development. 2010; 137: 1833–1842. doi: 10.1242/dev.047647 20431121

104. Kuzmanov A, Yochem J and Fay DS. Analysis of PHA-1 reveals a limited role in pharyngeal development and novel functions in other tissues. Genetics. 2014; 198: 259–268. doi: 10.1534/genetics.114.166876 25009149

105. Herold A, Teixeira L and Izaurralde E. Genome-wide analysis of nuclear mRNA export pathways in Drosophila. EMBO J. 2003; 22: 2472–2483. doi: 10.1093/emboj/cdg233 12743041

106. Mamon LA, Ginanova VR, Kliver SF, Yakimova AO, Atsapkina AA and Golubkova EV. RNA-binding proteins of the NXF (nuclear export factor) family and their connection with the cytoskeleton. Cytoskeleton (Hoboken). 2017; 74: 161–169.

107. Golubkova EV, Atsapkina AA and Mamon LA. The role of sbr/Dm nxf1 gene in syncytial development in Drosophila melanogaster. Cell and Tissue Biology. 2015; 9: 271–283.

108. Moore L.L., Morrison M., and Roth M.B. HCP-1, a protein involved in chromosome segregation, is localized to the centromere of mitotic chromosomes in Caenorhabditis elegans. The Journal of cell biology. 1999; 147: 471–480 doi: 10.1083/jcb.147.3.471 10545493

109. Cheeseman I.M., MacLeod I., Yates J.R. 3rd, Oegema K., and Desai A. (2005). The CENP-F-like proteins HCP-1 and HCP-2 target CLASP to kinetochores to mediate chromosome segregation. Current biology. 2005; 15: 771–777. doi: 10.1016/j.cub.2005.03.018 15854912

110. Golubkova EV, Markova EG, Markov AV, Avanesyan EO, Nokkala S and Mamon LA. Dm nxf1/sbr gene affects the formation of meiotic spindle in female Drosophila melanogaster. Chromosome Res. 2009; 17: 833–845. doi: 10.1007/s10577-009-9046-x 19779841

111. Yamazaki T, Fujiwara N, Yukinaga H, Ebisuya M, Shiki T, Kurihara T, Kioka N, Kambe T, Nagao M, Nishida E et al. The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression. Mol Biol Cell. 2010; 21: 2953–2965. doi: 10.1091/mbc.E09-10-0913 20573985

112. Bermejo R, Capra T, Jossen R, Colosio A, Frattini C, Carotenuto W, Cocito A, Doksani Y, Klein H, Gomez-Gonzalez B et al. The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores. Cell. 2011; 146: 233–246. doi: 10.1016/j.cell.2011.06.033 21784245

113. Kumar A, Mazzanti M, Mistrik M, Kosar M, Beznoussenko GV, Mironov AA, Garre M, Parazzoli D, Shivashankar GV, Scita G et al. ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell. 2014; 158: 633–646. doi: 10.1016/j.cell.2014.05.046 25083873

114. Rohner S, Kalck V, Wang X, Ikegami K, Lieb JD, Gasser SM and Meister P. Promoter- and RNA polymerase II-dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans. J Cell Biol. 2013; 200: 589–604. doi: 10.1083/jcb.201207024 23460676

115. Hurt JA and Silver PA. mRNA nuclear export and human disease. Dis Model Mech. 2008; 1: 103–108. doi: 10.1242/dmm.000745 19048072

116. Simon DN and Rout MP. Cancer and the nuclear pore complex. Adv Exp Med Biol. 2014; 773: 285–307. doi: 10.1007/978-1-4899-8032-8_13 24563353

117. Geuens T, Bouhy D and Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet. 2016; 135: 851–867. doi: 10.1007/s00439-016-1683-5 27215579

118. Hautbergue GM. RNA Nuclear Export: From Neurological Disorders to Cancer. Adv Exp Med Biol. 2017; 1007: 89–109. doi: 10.1007/978-3-319-60733-7_6 28840554

119. Wickramasinghe VO and Venkitaraman AR. RNA Processing and Genome Stability: Cause and Consequence. Mol Cell. 2016; 61: 496–505. doi: 10.1016/j.molcel.2016.02.001 26895423

120. Kumar RD, Searleman AC, Swamidass SJ, Griffith OL and Bose R. Statistically identifying tumor suppressors and oncogenes from pan-cancer genome-sequencing data. Bioinformatics. 2015; 31: 3561–3568. doi: 10.1093/bioinformatics/btv430 26209800

121. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974; 77: 71–94. 4366476

122. Hochbaum D, Ferguson AA and Fisher AL. Generation of transgenic C. elegans by biolistic transformation. J Vis Exp. 2010; 42.Pii2090.

123. Lanctot C and Meister P. Microscopic analysis of chromatin localization and dynamics in C. elegans. Methods Mol Biol. 2013; 1042: 153–172. doi: 10.1007/978-1-62703-526-2_11 23980006

124. Hardin J. Imaging embryonic morphogenesis in C. elegans. Methods Cell Biol. 2011; 106: 377–412. doi: 10.1016/B978-0-12-544172-8.00014-1 22118285

125. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227: 680–685. doi: 10.1038/227680a0 5432063

126. Rual JF, Ceron J, Koreth J, Hao T, Nicot AS, Hirozane-Kishikawa T, Vandenhaute J, Orkin SH, Hill DE, van den Heuvel S, Vidal M. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 2004;14: 2162–2168 doi: 10.1101/gr.2505604 15489339

127. Nieto C, Almendinger J, Gysi S, Gomez-Orte E, Kaech A, Hengartner MO, Schnabel R, Moreno S, Cabello J. ccz-1 mediates digestion of apoptotic corpses in C. elegans. J Cell Science. 2010; 123: 2001–2007. doi: 10.1242/jcs.062331 20519582

128. Doitsidou M, Poole RJ, Sarin S, Bigelow H and Hobert O. C. elegans mutant identification with a one-step whole-genome-sequencing and SNP mapping strategy. PLoS One. 2010; 5(11): e15435. doi: 10.1371/journal.pone.0015435 21079745

129. Love MI, Huber W and Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15: 550. doi: 10.1186/s13059-014-0550-8 25516281

130. Robinson MD, McCarthy DJ and Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010; 26: 139–140. doi: 10.1093/bioinformatics/btp616 19910308

131. Gomez-Orte E, Cornes E, Zheleva A, Saenz-Narciso B, de Toro M, Iniguez M, Lopez R, San-Juan JF, Ezcurra B, Sacristan B et al. Effect of the diet type and temperature on the C. elegans transcriptome. Oncotarget. 2018; 9: 9556–9571. doi: 10.18632/oncotarget.23563 29515753

132. Gomez-Orte E, Saenz-Narciso B, Zheleva A, Ezcurra B, de Toro M, Lopez R, Gastaca I, Nilsen H, Sacristán MP, Schnabel R, Cabello J. Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes. PLOS Genetics, 2019; 15(2): e1007981. doi: 10.1371/journal.pgen.1007981 30807579