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Mitosis in Neurons: Roughex and APC/C Maintain Cell Cycle Exit to Prevent Cytokinetic and Axonal Defects in Photoreceptor Neurons


The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.


Vyšlo v časopise: Mitosis in Neurons: Roughex and APC/C Maintain Cell Cycle Exit to Prevent Cytokinetic and Axonal Defects in Photoreceptor Neurons. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003049
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003049

Souhrn

The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.


Zdroje

1. AjiokaI, DyerMA (2008) A new model of tumor susceptibility following tumor suppressor gene inactivation. Cell Cycle 7: 735–740.

2. AjiokaI, MartinsRA, BayazitovIT, DonovanS, JohnsonDA, et al. (2007) Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131: 378–390.

3. FirthLC, BakerNE (2005) Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. Developmental Cell 8: 541–551.

4. Lopez-SanchezN, Ovejero-BenitoMC, BorregueroL, FradeJM (2011) Control of neuronal ploidy during vertebrate development. Results Probl Cell Differ 53: 547–563.

5. HeintzN (1993) Cell death and the cell cycle: a relationship between transformation and neurodegeneration? Trends in Biochemical Sciences 18: 157–159.

6. ZhuX, RainaAK, PerryG, SmithMA (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3: 219–226.

7. HerrupK, YangY (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nature Reviews Neuroscience 8: 368–378.

8. HoglingerGU, BreunigJJ, DepboyluC, RouauxC, MichelPP, et al. (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 104: 3585–3590.

9. MohC, KubiakJZ, BajicVP, ZhuX, SmithMA, et al. (2011) Cell cycle deregulation in the neurons of Alzheimer's disease. Results Probl Cell Differ 53: 565–576.

10. DuncanJE, GoldsteinLS (2006) The genetics of axonal transport and axonal transport disorders. PLoS Genet 2: e124 doi:10.1371/journal.pgen.0020124.

11. IkedaY, DickKA, WeatherspoonMR, GincelD, ArmbrustKR, et al. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genetics 38: 184–190.

12. StokinGB, GoldsteinLS (2006) Axonal transport and Alzheimer's disease. Annual Review of Biochemistry 75: 607–627.

13. LorenzoDN, LiMG, MischeSE, ArmbrustKR, RanumLP, et al. (2010) Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. The Journal of Cell Biology 189: 143–158.

14. ReadyDF, HansonTE, BenzerS (1976) Development of the Drosophila retina, a neurocrystalline lattice. Developmental Biology 53: 217–240.

15. Wolff T, Ready DF (1993) Pattern formation in the Drosophila retina. In: M. Bate AMA, editor. The Development of Drosophila melanogaster. Cold Spring Harbor, NY Cold Spring Harbor Laboratory Press. pp. 1277–1325.

16. BakerNE (2007) Patterning signals and proliferation in Drosophila imaginal discs. Current Opinion in Genetics & Development 17: 287–293.

17. MlodzikM, BakerNE, RubinGM (1990) Isolation and expression of scabrous, a gene regulating neurogenesis in Drosophila. Genes & Development 4: 1848–1861.

18. JarmanAP, GrellEH, AckermanL, JanLY, JanYN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369: 398–400.

19. JarmanAP, SunY, JanLY, JanYN (1995) Role of the proneural gene, atonal, in formation of Drosophila chordotonal organs and photoreceptors. Development 121: 2019–2030.

20. NoloR, AbbottLA, BellenHJ (2000) Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102: 349–362.

21. BakerNE (2002) Notch and the patterning of ommatidial founder cells in the developing Drosophila eye. Results and Problems in Cell Differentiation 35–58.

22. FrankfortBJ, MardonG (2002) R8 development in the Drosophila eye: a paradigm for neural selection and differentiation. Development 129: 1295–1306.

23. TomlinsonA, ReadyDF (1987) Neuronal differentiation in Drosophila ommatidium. Developmental Biology 120: 366–376.

24. FreemanM (1997) Cell determination strategies in the Drosophila eye. Development 124: 261–270.

25. Gaul U, editor (2002) The establishment of retinal connectivity Heidelberg, Berlin: Springer Verlag. 205–218 p.

26. TaylerTD, GarrityPA (2003) Axon targeting in the Drosophila visual system. Current Opinion in Neurobiology 13: 90–95.

27. GonczyP, ThomasBJ, DiNardoS (1994) roughex is a dose-dependent regulator of the second meiotic division during Drosophila spermatogenesis. Cell 77: 1015–1025.

28. ThomasBJ, GunningDA, ChoJ, ZipurskyL (1994) Cell cycle progression in the developing Drosophila eye: roughex encodes a novel protein required for the establishment of G1. Cell 77: 1003–1014.

29. DongX, ZavitzKH, ThomasBJ, LinM, CampbellS, et al. (1997) Control of G1 in the developing Drosophila eye: rca1 regulates Cyclin A. Genes & Development 11: 94–105.

30. ThomasBJ, ZavitzKH, DongX, LaneME, WeigmannK, et al. (1997) roughex down-regulates G2 cyclins in G1. Genes & Development 11: 1289–1298.

31. FoleyE, O'FarrellPH, SprengerF (1999) Rux is a cyclin-dependent kinase inhibitor (CKI) specific for mitotic cyclin-Cdk complexes. Current Biology : CB 9: 1392–1402.

32. FoleyE, SprengerF (2001) The cyclin-dependent kinase inhibitor Roughex is involved in mitotic exit in Drosophila. Current Biology : CB 11: 151–160.

33. KnoblichJA, LehnerCF (1993) Synergistic action of Drosophila cyclins A and B during the G2-M transition. The EMBO Journal 12: 65–74.

34. KnoblichJA, SauerK, JonesL, RichardsonH, SaintR, et al. (1994) Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell 77: 107–120.

35. SprengerF, YakubovichN, O'FarrellPH (1997) S-phase function of Drosophila cyclin A and its downregulation in G1 phase. Current Biology : CB 7: 488–499.

36. JacobsHW, KeidelE, LehnerCF (2001) A complex degradation signal in Cyclin A required for G1 arrest, and a C-terminal region for mitosis. The EMBO Journal 20: 2376–2386.

37. DietzlG, ChenD, SchnorrerF, SuKC, BarinovaY, et al. (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448: 151–156.

38. de NooijJC, HariharanIK (1995) Uncoupling cell fate determination from patterned cell division in the Drosophila eye. Science 270: 983–985.

39. AvedisovSN, KrasnoselskayaI, MortinM, ThomasBJ (2000) Roughex mediates G(1) arrest through a physical association with cyclin A. Mol Cell Biol 20: 8220–8229.

40. HarperJW, AdamiGR, WeiN, KeyomarsiK, ElledgeSJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816.

41. HarperJW, ElledgeSJ, KeyomarsiK, DynlachtB, TsaiLH, et al. (1995) Inhibition of cyclin-dependent kinases by p21. Molecular Biology of the Cell 6: 387–400.

42. RussoAA, JeffreyPD, PattenAK, MassagueJ, PavletichNP (1996) Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382: 325–331.

43. WangY, FisherJC, MathewR, OuL, OtienoS, et al. (2011) Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21. Nature Chemical Biology 7: 214–221.

44. EvansT, RosenthalET, YoungblomJ, DistelD, HuntT (1983) Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33: 389–396.

45. LeeT, LuoL (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22: 451–461.

46. WhiteNM, JarmanAP (2000) Drosophila atonal controls photoreceptor R8-specific properties and modulates both receptor tyrosine kinase and Hedgehog signalling. Development 127: 1681–1689.

47. de la CruzAF, EdgarBA (2008) Flow cytometric analysis of Drosophila cells. Methods in Molecular Biology 420: 373–389.

48. Foe V, Odell GM, Edgar B (1993) Mitosis and morphegenesis in the Drosophila embryo. Point and counterpoint. In: M. Bate AMA, editor. The Development of Drosophila melanogaster. Cold Spring Harbor, NY Cold Spring Harbor Laboratory Press. pp. 1277–1325.

49. KarsentiE, VernosI (2001) The mitotic spindle: a self-made machine. Science 294: 543–547.

50. GoshimaG (2010) Assessment of mitotic spindle phenotypes in Drosophila S2 cells. Methods in Cell Biology 97: 259–275.

51. LuB, RoegiersF, JanLY, JanYN (2001) Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature 409: 522–525.

52. den ElzenN, ButteryCV, MaddugodaMP, RenG, YapAS (2009) Cadherin adhesion receptors orient the mitotic spindle during symmetric cell division in mammalian epithelia. Molecular Biology of the Cell 20: 3740–3750.

53. NeufeldTP, RubinGM (1994) The Drosophila peanut gene is required for cytokinesis and encodes a protein similar to yeast putative bud neck filament proteins. Cell 77: 371–379.

54. StearnsT, EvansL, KirschnerM (1991) Gamma-tubulin is a highly conserved component of the centrosome. Cell 65: 825–836.

55. RaffJW, KelloggDR, AlbertsBM (1993) Drosophila gamma-tubulin is part of a complex containing two previously identified centrosomal MAPs. The Journal of Cell Biology 121: 823–835.

56. BastoR, LauJ, VinogradovaT, GardiolA, WoodsCG, et al. (2006) Flies without centrioles. Cell 125: 1375–1386.

57. BuendiaB, DraettaG, KarsentiE (1992) Regulation of the microtubule nucleating activity of centrosomes in Xenopus egg extracts: role of cyclin A-associated protein kinase. The Journal of Cell Biology 116: 1431–1442.

58. LeeA, TreismanJE (2004) Excessive Myosin activity in mbs mutants causes photoreceptor movement out of the Drosophila eye disc epithelium. Molecular Biology of the Cell 15: 3285–3295.

59. AcquavivaC, PinesJ (2006) The anaphase-promoting complex/cyclosome: APC/C. Journal of Cell Science 119: 2401–2404.

60. KarpilowJ, KolodkinA, BorkT, VenkateshT (1989) Neuronal development in the Drosophila compound eye: rap gene function is required in photoreceptor cell R8 for ommatidial pattern formation. Genes & Development 3: 1834–1844.

61. PimentelAC, VenkateshTR (2005) rap gene encodes Fizzy-related protein (Fzr) and regulates cell proliferation and pattern formation in the developing Drosophila eye-antennal disc. Developmental Biology 285: 436–446.

62. Tanaka-MatakatsuM, ThomasBJ, DuW (2007) Mutation of the Apc1 homologue shattered disrupts normal eye development by disrupting G1 cell cycle arrest and progression through mitosis. Developmental Biology 309: 222–235.

63. AvedisovSN, RogozinIB, KooninEV, ThomasBJ (2001) Rapid evolution of a cyclin A inhibitor gene, roughex, in Drosophila. Molecular Biology and Evolution 18: 2110–2118.

64. LukasC, SorensenCS, KramerE, Santoni-RugiuE, LindenegC, et al. (1999) Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature 401: 815–818.

65. BlancoMA, Sanchez-DiazA, de PradaJM, MorenoS (2000) APC(ste9/srw1) promotes degradation of mitotic cyclins in G(1) and is inhibited by cdc2 phosphorylation. The EMBO Journal 19: 3945–3955.

66. BakerNE, YuSY (2001) The EGF receptor defines domains of cell cycle progression and survival to regulate cell number in the developing Drosophila eye. Cell 104: 699–708.

67. ButtittaLA, KatzaroffAJ, EdgarBA (2010) A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo. The Journal of Cell Biology 189: 981–996.

68. KosakoH, YoshidaT, MatsumuraF, IshizakiT, NarumiyaS, InagakiM (2000) Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow. Oncogene 19: 6059–6064.

69. SommaMP, FasuloB, CenciG, CundariE, GattiM (2002) Molecular dissection of cytokinesis by RNA interference in Drosophila cultured cells. Molecular Biology of the Cell 13: 2448–2460.

70. ShiQ, KingRW (2005) Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 437: 1038–1042.

71. WeberT, CorbettMK, ChowLM, ValentineMB, BakerSJ, et al. (2008) Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proceedings of the National Academy of Sciences of the United States of America 105: 781–785.

72. TomlinsonA (1985) The cellular dynamics of pattern formation in the eye of Drosophila. Journal of Embryology and Experimental Morphology 89: 313–331.

73. SharpDJ, RogersGC, ScholeyJM (2000) Cytoplasmic dynein is required for poleward chromosome movement during mitosis in Drosophila embryos. Nature Cell Biology 2: 922–930.

74. FanSS, ReadyDF (1997) Glued participates in distinct microtubule-based activities in Drosophila eye development. Development 124: 1497–1507.

75. AllenMJ, ShanX, CaruccioP, FroggettSJ, MoffatKG, et al. (1999) Targeted expression of truncated glued disrupts giant fiber synapse formation in Drosophila. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 19: 9374–9384.

76. WhitedJL, CassellA, BrouilletteM, GarrityPA (2004) Dynactin is required to maintain nuclear position within postmitotic Drosophila photoreceptor neurons. Development 131: 4677–4686.

77. TsujikawaM, OmoriY, BiyanwilaJ, MalickiJ (2007) Mechanism of positioning the cell nucleus in vertebrate photoreceptors. Proceedings of the National Academy of Sciences of the United States of America 104: 14819–14824.

78. ZhuX, SiedlakSL, WangY, PerryG, CastellaniRJ, et al. (2008) Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol Appl Neurobiol 34: 457–465.

79. Perkins LA, Shim HS, Perrimon N. Initial TRiP stock collection.

80. SaxtonWM, HicksJ, GoldsteinLS, RaffEC (1991) Kinesin heavy chain is essential for viability and neuromuscular functions in Drosophila, but mutants show no defects in mitosis. Cell 64: 1093–1102.

81. Hales K. (2008) P{Sep2-GFP.SG}3.

82. BierE, VaessinH, ShepherdS, LeeK, McCallK, et al. (1989) Searching for pattern and mutation in the Drosophila genome with a P-lacZ vector. Genes & Development 3: 1273–1287.

83. FirthLC, LiW, ZhangH, BakerNE (2006) Analyses of RAS regulation of eye development in Drosophila melanogaster. Methods in Enzymology 407: 711–721.

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