Anaplastic Lymphoma Kinase Acts in the Mushroom Body to Negatively Regulate Sleep


Animal and human studies suggest that sleep has a profound impact on learning and memory. However, little is known about the molecular pathways linking these phenomena. We report that mutations in the Drosophila Anaplastic lymphoma kinase (Alk) gene, an ortholog of a human oncogene ALK, cause increased sleep. ALK is required for sleep suppression in the mushroom body, a structure important for both sleep and memory. ALK generally activates the Ras/ERK pathway, which is negatively regulated by Neurofibromin 1 (NF1). Mutations in Nf1 are the causes of the common neurological disorder Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 live births. We find that male flies lacking the NF1 protein have reduced sleep, a phenotype opposite that of Alk flies. Interestingly, even though mutations in Nf1 don’t always cause short sleep in female flies, they suppress the sleep increase induced by ALK inactivation. Previous studies have shown that Alk and Nf1 play antagonistic roles in learning and that both genes regulate synaptic growth. Thus Alk and Nf1 interact to regulate both sleep and learning, suggesting that the two processes share a common pathway. Our results support a model in which changes in synaptic plasticity during sleep promote learning and memory.


Vyšlo v časopise: Anaplastic Lymphoma Kinase Acts in the Mushroom Body to Negatively Regulate Sleep. PLoS Genet 11(11): e32767. doi:10.1371/journal.pgen.1005611
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005611

Souhrn

Animal and human studies suggest that sleep has a profound impact on learning and memory. However, little is known about the molecular pathways linking these phenomena. We report that mutations in the Drosophila Anaplastic lymphoma kinase (Alk) gene, an ortholog of a human oncogene ALK, cause increased sleep. ALK is required for sleep suppression in the mushroom body, a structure important for both sleep and memory. ALK generally activates the Ras/ERK pathway, which is negatively regulated by Neurofibromin 1 (NF1). Mutations in Nf1 are the causes of the common neurological disorder Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 live births. We find that male flies lacking the NF1 protein have reduced sleep, a phenotype opposite that of Alk flies. Interestingly, even though mutations in Nf1 don’t always cause short sleep in female flies, they suppress the sleep increase induced by ALK inactivation. Previous studies have shown that Alk and Nf1 play antagonistic roles in learning and that both genes regulate synaptic growth. Thus Alk and Nf1 interact to regulate both sleep and learning, suggesting that the two processes share a common pathway. Our results support a model in which changes in synaptic plasticity during sleep promote learning and memory.


Zdroje

1. Hartse KM (2011) The phylogeny of sleep. Handb Clin Neurol 98: 97–109. doi: 10.1016/B978-0-444-52006-7.00007-1 21056182

2. Wang G, Grone B, Colas D, Appelbaum L, Mourrain P (2011) Synaptic plasticity in sleep: learning, homeostasis and disease. Trends Neurosci 34: 452–463. doi: 10.1016/j.tins.2011.07.005 21840068

3. Tononi G, Cirelli C (2014) Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81: 12–34. doi: 10.1016/j.neuron.2013.12.025 24411729

4. Vyazovskiy VV, Cirelli C, Pfister-Genskow M, Faraguna U, Tononi G (2008) Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci 11: 200–208. doi: 10.1038/nn2035 18204445

5. Gilestro GF, Tononi G, Cirelli C (2009) Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science 324: 109–112. doi: 10.1126/science.1166673 19342593

6. Stickgold R, Hobson JA, Fosse R, Fosse M (2001) Sleep, learning, and dreams: off-line memory reprocessing. Science 294: 1052–1057. 11691983

7. Florian C, Vecsey CG, Halassa MM, Haydon PG, Abel T (2011) Astrocyte-derived adenosine and A1 receptor activity contribute to sleep loss-induced deficits in hippocampal synaptic plasticity and memory in mice. J Neurosci 31: 6956–6962. doi: 10.1523/JNEUROSCI.5761-10.2011 21562257

8. Seugnet L, Suzuki Y, Vine L, Gottschalk L, Shaw PJ (2008) D1 receptor activation in the mushroom bodies rescues sleep-loss-induced learning impairments in Drosophila. Curr Biol 18: 1110–1117. doi: 10.1016/j.cub.2008.07.028 18674913

9. Li X, Yu F, Guo A (2009) Sleep deprivation specifically impairs short-term olfactory memory in Drosophila. Sleep 32: 1417–1424. 19928381

10. Bushey D, Cirelli C (2011) From genetics to structure to function: exploring sleep in Drosophila. Int Rev Neurobiol 99: 213–244. doi: 10.1016/B978-0-12-387003-2.00009-4 21906542

11. Palmer RH, Vernersson E, Grabbe C, Hallberg B (2009) Anaplastic lymphoma kinase: signalling in development and disease. Biochem J 420: 345–361. doi: 10.1042/BJ20090387 19459784

12. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, et al. (1997) Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14: 439–449. 9053841

13. Loren CE, Scully A, Grabbe C, Edeen PT, Thomas J, et al. (2001) Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo. Genes Cells 6: 531–544. 11442633

14. Gouzi JY, Moressis A, Walker JA, Apostolopoulou AA, Palmer RH, et al. (2011) The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning. PLoS Genet 7: e1002281. doi: 10.1371/journal.pgen.1002281 21949657

15. Lee HH, Norris A, Weiss JB, Frasch M (2003) Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 425: 507–512. 14523446

16. Englund C, Loren CE, Grabbe C, Varshney GK, Deleuil F, et al. (2003) Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion. Nature 425: 512–516. 14523447

17. Bazigou E, Apitz H, Johansson J, Loren CE, Hirst EM, et al. (2007) Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila. Cell 128: 961–975. 17350579

18. Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC, et al. (2011) Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell 146: 435–447. doi: 10.1016/j.cell.2011.06.040 21816278

19. Rohrbough J, Kent KS, Broadie K, Weiss JB (2013) Jelly Belly trans-synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture. Dev Neurobiol 73: 189–208. doi: 10.1002/dneu.22056 22949158

20. Bilsland JG, Wheeldon A, Mead A, Znamenskiy P, Almond S, et al. (2008) Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacology 33: 685–700. 17487225

21. Weiss JB, Xue C, Benice T, Xue L, Morris SW, et al. (2012) Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis. Pharmacol Biochem Behav 100: 566–574. doi: 10.1016/j.pbb.2011.10.024 22079349

22. Williams JA, Su HS, Bernards A, Field J, Sehgal A (2001) A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK. Science 293: 2251–2256. 11567138

23. Loren CE, Englund C, Grabbe C, Hallberg B, Hunter T, et al. (2003) A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster. EMBO Rep 4: 781–786. 12855999

24. Zimmerman JE, Chan MT, Jackson N, Maislin G, Pack AI. (2012) Genetic background has a major impact on differences in sleep resulting from environmental influences in Drosophila. Sleep 35:545–57. doi: 10.5665/sleep.1744 22467993

25. Ryder E, Blows F, Ashburner M, Bautista-Llacer R, Coulson D, et al. (2004) The DrosDel collection: a set of P-element insertions for generating custom chromosomal aberrations in Drosophila melanogaster. Genetics 167:797–813. 15238529

26. Low KH, Lim C, Ko HW, Edery I (2008) Natural variation in the splice site strength of a clock gene and species-specific thermal adaptation. Neuron 60: 1054–1067. doi: 10.1016/j.neuron.2008.10.048 19109911

27. Zimmerman JE, Raizen DM, Maycock MH, Maislin G, Pack AI (2008) A video method to study Drosophila sleep. Sleep 31: 1587–1598. 19014079

28. Faville R, Kottler B, Goodhill GJ, Shaw PJ, van Swinderen B (2015) How deeply does your mutant sleep? Probing arousal to better understand sleep defects in Drosophila. Sci Rep 5: 8454. doi: 10.1038/srep08454 25677943

29. Barone MC, Bohmann D (2013) Assessing neurodegenerative phenotypes in Drosophila dopaminergic neurons by climbing assays and whole brain immunostaining. J Vis Exp: e50339. doi: 10.3791/50339 23644755

30. Hendricks JC, Finn SM, Panckeri KA, Chavkin J, Williams JA, et al. (2000) Rest in Drosophila is a sleep-like state. Neuron 25: 129–138. 10707978

31. Andretic R, van Swinderen B, Greenspan RJ (2005) Dopaminergic modulation of arousal in Drosophila. Curr Biol 15: 1165–1175. 16005288

32. Kume K, Kume S, Park SK, Hirsh J, Jackson FR (2005) Dopamine is a regulator of arousal in the fruit fly. J Neurosci 25: 7377–7384. 16093388

33. Joiner WJ, Crocker A, White BH, Sehgal A (2006) Sleep in Drosophila is regulated by adult mushroom bodies. Nature 441: 757–760. 16760980

34. Pitman JL, McGill JJ, Keegan KP, Allada R (2006) A dynamic role for the mushroom bodies in promoting sleep in Drosophila. Nature 441: 753–756. 16760979

35. Donlea JM, Thimgan MS, Suzuki Y, Gottschalk L, Shaw PJ (2011) Inducing sleep by remote control facilitates memory consolidation in Drosophila. Science 332: 1571–1576. doi: 10.1126/science.1202249 21700877

36. Foltenyi K, Greenspan RJ, Newport JW (2007) Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nat Neurosci 10: 1160–1167. 17694052

37. Crocker A, Shahidullah M, Levitan IB, Sehgal A (2010) Identification of a neural circuit that underlies the effects of octopamine on sleep:wake behavior. Neuron 65: 670–681. doi: 10.1016/j.neuron.2010.01.032 20223202

38. Parisky KM, Agosto J, Pulver SR, Shang Y, Kuklin E, et al. (2008) PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit. Neuron 60: 672–682. doi: 10.1016/j.neuron.2008.10.042 19038223

39. Sheeba V, Fogle KJ, Kaneko M, Rashid S, Chou YT, et al. (2008) Large ventral lateral neurons modulate arousal and sleep in Drosophila. Curr Biol 18: 1537–1545. doi: 10.1016/j.cub.2008.08.033 18771923

40. McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302: 1765–1768. 14657498

41. Krashes MJ, Keene AC, Leung B, Armstrong JD, Waddell S (2007) Sequential use of mushroom body neuron subsets during drosophila odor memory processing. Neuron 53: 103–115. 17196534

42. Aso Y, Grubel K, Busch S, Friedrich AB, Siwanowicz I, et al. (2009) The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet 23: 156–172. doi: 10.1080/01677060802471718 19140035

43. Jenett A, Rubin GM, Ngo TT, Shepherd D, Murphy C, et al. (2012) A GAL4-driver line resource for Drosophila neurobiology. Cell Rep 2: 991–1001. doi: 10.1016/j.celrep.2012.09.011 23063364

44. Licis AK, Vallorani A, Gao F, Chen C, Lenox J, et al. (2013) Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1. J Child Neurol 28: 1400–1405. 24065580

45. Leschziner GD, Golding JF, Ferner RE (2013) Sleep disturbance as part of the neurofibromatosis type 1 phenotype in adults. Am J Med Genet A 161A: 1319–1322. doi: 10.1002/ajmg.a.35915 23636844

46. The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, et al. (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276: 791–794. 9115203

47. Guo HF, Tong J, Hannan F, Luo L, Zhong Y (2000) A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 403: 895–898. 10706287

48. Shinkai Y, Yamamoto Y, Fujiwara M, Tabata T, Murayama T, et al. (2011) Behavioral choice between conflicting alternatives is regulated by a receptor guanylyl cyclase, GCY-28, and a receptor tyrosine kinase, SCD-2, in AIA interneurons of Caenorhabditis elegans. J Neurosci 31: 3007–3015. doi: 10.1523/JNEUROSCI.4691-10.2011 21414922

49. Lasek AW, Gesch J, Giorgetti F, Kharazia V, Heberlein U (2011) Alk is a transcriptional target of LMO4 and ERalpha that promotes cocaine sensitization and reward. J Neurosci 31: 14134–14141. doi: 10.1523/JNEUROSCI.3415-11.2011 21976498

50. Lasek AW, Lim J, Kliethermes CL, Berger KH, Joslyn G, et al. (2011) An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol. PLoS One 6: e22636. doi: 10.1371/journal.pone.0022636 21799923

51. Vanderheyden WM, Gerstner JR, Tanenhaus A, Yin JC, Shaw PJ (2013) ERK phosphorylation regulates sleep and plasticity in Drosophila. PLoS One 8: e81554. doi: 10.1371/journal.pone.0081554 24244744

52. Buchanan ME, Davis RL (2010) A distinct set of Drosophila brain neurons required for neurofibromatosis type 1-dependent learning and memory. J Neurosci 30: 10135–10143. doi: 10.1523/JNEUROSCI.0283-10.2010 20668197

53. Harbison ST, McCoy LJ, Mackay TF (2013) Genome-wide association study of sleep in Drosophila melanogaster. BMC Genomics 14: 281. doi: 10.1186/1471-2164-14-281 23617951

54. Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, et al. (2014) Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 75: 309–316. doi: 10.1002/ana.24093 24375753

55. Bushey D, Tononi G, Cirelli C (2011) Sleep and synaptic homeostasis: structural evidence in Drosophila. Science 332: 1576–1581. doi: 10.1126/science.1202839 21700878

56. Bushey D, Tononi G, Cirelli C (2009) The Drosophila fragile X mental retardation gene regulates sleep need. J Neurosci 29: 1948–1961. doi: 10.1523/JNEUROSCI.4830-08.2009 19228950

57. Rohrbough J, Broadie K (2010) Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap. Development 137: 3523–3533. doi: 10.1242/dev.047878 20876658

58. Tsai PI, Wang M, Kao HH, Cheng YJ, Walker JA, et al. (2012) Neurofibromin mediates FAK signaling in confining synapse growth at Drosophila neuromuscular junctions. J Neurosci 32: 16971–16981. doi: 10.1523/JNEUROSCI.1756-12.2012 23175848

59. Walker JA, Gouzi JY, Long JB, Huang S, Maher RC, et al. (2013) Genetic and functional studies implicate synaptic overgrowth and ring gland cAMP/PKA signaling defects in the Drosophila melanogaster neurofibromatosis-1 growth deficiency. PLoS Genet 9: e1003958. doi: 10.1371/journal.pgen.1003958 24278035

60. Cavanaugh DJ, Geratowski JD, Wooltorton JR, Spaethling JM, Hector CE, et al. (2014) Identification of a circadian output circuit for rest:activity rhythms in Drosophila. Cell 157: 689–701. doi: 10.1016/j.cell.2014.02.024 24766812

61. Donlea JM, Ramanan N, Shaw PJ (2009) Use-dependent plasticity in clock neurons regulates sleep need in Drosophila. Science 324: 105–108. doi: 10.1126/science.1166657 19342592

62. Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415. 8223268

63. Gohl DM, Silies MA, Gao XJ, Bhalerao S, Luongo FJ, et al. (2011) A versatile in vivo system for directed dissection of gene expression patterns. Nat Methods 8: 231–237. 21473015

64. Salvaterra P.M., Kitamoto T. (2001). Drosophila cholinergic neurons and processes visualized with Gal4/UAS-GFP. Brain Res. Gene Expr. Patterns 1: 73–82.

65. Siegmund T, Korge G (2001) Innervation of the ring gland of Drosophila melanogaster. J Comp Neurol 431: 481–491. 11223816

66. Kayser MS, Yue Z, Sehgal A (2014). A critical period of sleep for development of courtship circuitry and behavior in Drosophila. Science 344:269–74. doi: 10.1126/science.1250553 24744368

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa