Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila


Autoři: Lanikea B. King aff001;  Tamara Boto aff001;  Valentina Botero aff001;  Ari M. Aviles aff001;  Breanna M. Jomsky aff001;  Chevara Joseph aff001;  James A. Walker aff003;  Seth M. Tomchik aff001
Působiště autorů: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, United States of America aff001;  Honors College, Florida Atlantic University, Jupiter, Florida, United States of America aff002;  Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America aff003
Vyšlo v časopise: Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila. PLoS Genet 16(7): e32767. doi:10.1371/journal.pgen.1008920
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008920

Souhrn

Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model. Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during development. Furthermore, intact Nf1 Ras GAP-related domain signaling was required to maintain normal grooming. The requirement for Nf1 was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits. Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive key Nf1-mediated behavioral alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.

Klíčová slova:

Behavior – Central nervous system – Drosophila melanogaster – Neural pathways – Neurofibromatosis type 1 – Neurons – Ras signaling – RNA interference – Genetics


Zdroje

1. Hyman SL, Shores A, North KN. (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65: 1037–44. doi: 10.1212/01.wnl.0000179303.72345.ce 16217056

2. Diggs-Andrews KA, Gutmann DH. (2013) Modeling cognitive dysfunction in neurofibromatosis-1. Trends Neurosci 36: 237–47. doi: 10.1016/j.tins.2012.12.002 23312374

3. Constantino JN, Zhang Y, Holzhauer K, Sant S, Long K, Vallorani A, Malik L, Gutmann DH. (2015) Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type I. J Pediatr 167: 621–6 e1. doi: 10.1016/j.jpeds.2015.04.075 26051969

4. Eijk S, Mous SE, Dieleman GC, Dierckx B, Rietman AB, de Nijs PFA, Ten Hoopen LW, van Minkelen R, Elgersma Y, Catsman-Berrevoets CE, Oostenbrink R, Legerstee JS. (2018) Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1). J Autism Dev Disord, doi: 10.1007/s10803-018-3478-0 29423604

5. Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG, Huson SM. (2013) Neurofibromatosis type 1 and autism spectrum disorder. Pediatrics 132: e1642–8. doi: 10.1542/peds.2013-1868 24190681

6. Hyman SL, Shores EA, North KN. (2006) Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol 48: 973–7. doi: 10.1017/S0012162206002131 17109785

7. Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN. (2016) Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry 73: 1276–84. doi: 10.1001/jamapsychiatry.2016.2600 27760236

8. Plasschaert E, Van Eylen L, Descheemaeker MJ, Noens I, Legius E, Steyaert J. (2016) Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning. Am J Med Genet B Neuropsychiatr Genet 171B: 348–62. doi: 10.1002/ajmg.b.32414 26773288

9. Walsh KS, Velez JI, Kardel PG, Imas DM, Muenke M, Packer RJ, Castellanos FX, Acosta MT. (2013) Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 55: 131–8. doi: 10.1111/dmcn.12038 23163951

10. Payne JM. (2013) Autism spectrum disorder symptomatology in children with neurofibromatosis type 1. Dev Med Child Neurol 55: 100–1. doi: 10.1111/dmcn.12075 23320572

11. Ozonoff S. (1999) Cognitive impairment in neurofibromatosis type 1. Am J Med Genet 89: 45–52. 10469436

12. Cichowski K, Jacks T. (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104: 593–604. doi: 10.1016/s0092-8674(01)00245-8 11239415

13. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O'Connell P, Cawthon RM, et al. (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63: 843–9. doi: 10.1016/0092-8674(90)90150-d 2121370

14. Oliveira AF, Yasuda R. (2014) Neurofibromin is the major ras inactivator in dendritic spines. J Neurosci 34: 776–83. doi: 10.1523/JNEUROSCI.3096-13.2014 24431436

15. Brown JA, Gianino SM, Gutmann DH. (2010) Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity. J Neurosci 30: 5579–89. doi: 10.1523/JNEUROSCI.3994-09.2010 20410111

16. The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, Gusella JF, Hariharan IK, Bernards A. (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276: 791–4. doi: 10.1126/science.276.5313.791 9115203

17. Walker JA, Gouzi JY, Long JB, Huang S, Maher RC, Xia H, Khalil K, Ray A, Van Vactor D, Bernards R, Bernards A. (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

18. Tong J, Hannan F, Zhu Y, Bernards A, Zhong Y. (2002) Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci 5: 95–6. doi: 10.1038/nn792 11788835

19. Xie K, Colgan LA, Dao MT, Muntean BS, Sutton LP, Orlandi C, Boye SL, Boye SE, Shih CC, Li Y, Xu B, Smith RG, Yasuda R, Martemyanov KA. (2016) NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. Curr Biol 26: 2992–3003. doi: 10.1016/j.cub.2016.09.010 27773571

20. Diggs-Andrews KA, Tokuda K, Izumi Y, Zorumski CF, Wozniak DF, Gutmann DH. (2013) Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol 73: 309–15. doi: 10.1002/ana.23793 23225063

21. Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA. (2014) Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Rep 8: 1265–70. doi: 10.1016/j.celrep.2014.07.054 25176649

22. Ryu HH, Lee YS. (2016) Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders. Neurobiol Learn Mem 135: 13–21. doi: 10.1016/j.nlm.2016.06.006 27296701

23. Zhong J. (2016) RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction. Biol Chem 397: 215–22. doi: 10.1515/hsz-2015-0270 26760308

24. Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, Gutmann DH. (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63: 8573–7. 14695164

25. Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW. (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/—and c-kit-dependent bone marrow. Cell 135: 437–48. doi: 10.1016/j.cell.2008.08.041 18984156

26. Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH, Parada LF, Mody I, Silva AJ. (2008) Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135: 549–60. doi: 10.1016/j.cell.2008.09.060 18984165

27. Sutton LP, Muntean BS, Ostrovskaya O, Zucca S, Dao M, Orlandi C, Song C, Xie K, Martemyanov KA. (2019) NF1-cAMP signaling dissociates cell type-specific contributions of striatal medium spiny neurons to reward valuation and motor control. PLoS Biol 17: e3000477. doi: 10.1371/journal.pbio.3000477 31600280

28. Buchanan ME, Davis RL. (2010) A distinct set of Drosophila brain neurons required for neurofibromatosis type 1-dependent learning and memory. J Neurosci 30: 10135–43. doi: 10.1523/JNEUROSCI.0283-10.2010 20668197

29. Walker JA, Tchoudakova AV, McKenney PT, Brill S, Wu D, Cowley GS, Hariharan IK, Bernards A. (2006) Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons. Genes Dev 20: 3311–23. doi: 10.1101/gad.1466806 17114577

30. King LB, Koch M, Murphy KR, Velazquez Y, Ja WW, Tomchik SM. (2016) Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila. G3 (Bethesda) 6: 1083–93.

31. Hampel S, Franconville R, Simpson JH, Seeds AM. (2015) A neural command circuit for grooming movement control. Elife 4: e08758. doi: 10.7554/eLife.08758 26344548

32. Namiki S, Dickinson MH, Wong AM, Korff W, Card GM. (2018) The functional organization of descending sensory-motor pathways in Drosophila. Elife 7.

33. Cande J, Namiki S, Qiu J, Korff W, Card GM, Shaevitz JW, Stern DL, Berman GJ. (2018) Optogenetic dissection of descending behavioral control in Drosophila. Elife 7.

34. Yellman C, Tao H, He B, Hirsh J. (1997) Conserved and sexually dimorphic behavioral responses to biogenic amines in decapitated Drosophila. Proc Natl Acad Sci U S A 94: 4131–6. doi: 10.1073/pnas.94.8.4131 9108117

35. Hampel S, McKellar CE, Simpson JH, Seeds AM. (2017) Simultaneous activation of parallel sensory pathways promotes a grooming sequence in Drosophila. Elife 6.

36. Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson BJ. (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448: 151–6. doi: 10.1038/nature05954 17625558

37. Simpson JH. (2016) Rationally subdividing the fly nervous system with versatile expression reagents. J Neurogenet 30: 185–94. doi: 10.1080/01677063.2016.1248761 27846759

38. Clyne JD, Miesenbock G. (2008) Sex-specific control and tuning of the pattern generator for courtship song in Drosophila. Cell 133: 354–63. doi: 10.1016/j.cell.2008.01.050 18423205

39. Stowers RS. (2011) An efficient method for recombineering GAL4 and QF drivers. Fly (Austin) 5: 371–8.

40. Robb S, Cheek TR, Hannan FL, Hall LM, Midgley JM, Evans PD. (1994) Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems. EMBO J 13: 1325–30. 8137817

41. Ratner N, Miller SJ. (2015) A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15: 290–301. doi: 10.1038/nrc3911 25877329

42. Guo HF, The I, Hannan F, Bernards A, Zhong Y. (1997) Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276: 795–8. doi: 10.1126/science.276.5313.795 9115204

43. Guo HF, Tong J, Hannan F, Luo L, Zhong Y. (2000) A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 403: 895–8. doi: 10.1038/35002593 10706287

44. Dasgupta B, Dugan LL, Gutmann DH. (2003) The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes. J Neurosci 23: 8949–54. doi: 10.1523/JNEUROSCI.23-26-08949.2003 14523097

45. Tong JJ, Schriner SE, McCleary D, Day BJ, Wallace DC. (2007) Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster. Nat Genet 39: 476–85. doi: 10.1038/ng2004 17369827

46. Tsai PI, Wang M, Kao HH, Cheng YJ, Walker JA, Chen RH, Chien CT. (2012) Neurofibromin mediates FAK signaling in confining synapse growth at Drosophila neuromuscular junctions. J Neurosci 32: 16971–81. doi: 10.1523/JNEUROSCI.1756-12.2012 23175848

47. Klose A, Ahmadian MR, Schuelke M, Scheffzek K, Hoffmeyer S, Gewies A, Schmitz F, Kaufmann D, Peters H, Wittinghofer A, Nurnberg P. (1998) Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum Mol Genet 7: 1261–8. doi: 10.1093/hmg/7.8.1261 9668168

48. McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL. (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302: 1765–8. doi: 10.1126/science.1089035 14657498

49. Ma Z, Stork T, Bergles DE, Freeman MR. (2016) Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539: 428–32. doi: 10.1038/nature20145 27828941

50. Schutzler N, Girwert C, Hugli I, Mohana G, Roignant JY, Ryglewski S, Duch C. (2019) Tyramine action on motoneuron excitability and adaptable tyramine/octopamine ratios adjust Drosophila locomotion to nutritional state. Proc Natl Acad Sci U S A 116: 3805–10. doi: 10.1073/pnas.1813554116 30808766

51. Li HH, Kroll JR, Lennox SM, Ogundeyi O, Jeter J, Depasquale G, Truman JW. (2014) A GAL4 driver resource for developmental and behavioral studies on the larval CNS of Drosophila. Cell Rep 8: 897–908. doi: 10.1016/j.celrep.2014.06.065 25088417

52. Jenett A, Rubin GM, Ngo TT, Shepherd D, Murphy C, Dionne H, Pfeiffer BD, Cavallaro A, Hall D, Jeter J, Iyer N, Fetter D, Hausenfluck JH, Peng H, Trautman ET, Svirskas RR, Myers EW, Iwinski ZR, Aso Y, DePasquale GM, Enos A, Hulamm P, Lam SC, Li HH, Laverty TR, Long F, Qu L, Murphy SD, Rokicki K, Safford T, Shaw K, Simpson JH, Sowell A, Tae S, Yu Y, Zugates CT. (2012) A GAL4-driver line resource for Drosophila neurobiology. Cell Rep 2: 991–1001. doi: 10.1016/j.celrep.2012.09.011 23063364

53. Seeds AM, Ravbar P, Chung P, Hampel S, Midgley FM Jr., Mensh BD, Simpson JH. (2014) A suppression hierarchy among competing motor programs drives sequential grooming in Drosophila. Elife 3: e02951. doi: 10.7554/eLife.02951 25139955

54. Truman JW. (1990) Metamorphosis of the central nervous system of Drosophila. J Neurobiol 21: 1072–84. doi: 10.1002/neu.480210711 1979610

55. Truman JW. (2019) The Evolution of Insect Metamorphosis. Curr Biol 29: R1252–R68. doi: 10.1016/j.cub.2019.10.009 31794762

56. Lin S, Marin EC, Yang CP, Kao CF, Apenteng BA, Huang Y, O'Connor MB, Truman JW, Lee T. (2013) Extremes of lineage plasticity in the Drosophila brain. Curr Biol 23: 1908–13. doi: 10.1016/j.cub.2013.07.074 24055154

57. Mayseless O, Berns DS, Yu XM, Riemensperger T, Fiala A, Schuldiner O. (2018) Developmental Coordination during Olfactory Circuit Remodeling in Drosophila. Neuron 99: 1204–15 e5. doi: 10.1016/j.neuron.2018.07.050 30146303

58. Sopko R, Perrimon N. (2013) Receptor tyrosine kinases in Drosophila development. Cold Spring Harb Perspect Biol 5.

59. 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: 507–12. doi: 10.1038/nature01916 14523446

60. Bazigou E, Apitz H, Johansson J, Loren CE, Hirst EM, Chen PL, Palmer RH, Salecker I. (2007) Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila. Cell 128: 961–75. doi: 10.1016/j.cell.2007.02.024 17350579

61. Rohrbough J, Broadie K. (2010) Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap. Development 137: 3523–33. doi: 10.1242/dev.047878 20876658

62. 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

63. Walker JA, Bernards A. (2014) A Drosophila screen identifies neurofibromatosis-1 genetic modifiers involved in systemic and synaptic growth. Rare Dis 2: e28341. doi: 10.4161/rdis.28341 25054093

64. Simon MA, Bowtell DD, Dodson GS, Laverty TR, Rubin GM. (1991) Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67: 701–16. doi: 10.1016/0092-8674(91)90065-7 1934068

65. Li W, Cui Y, Kushner SA, Brown RA, Jentsch JD, Frankland PW, Cannon TD, Silva AJ. (2005) The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 15: 1961–7. doi: 10.1016/j.cub.2005.09.043 16271875


Článek vyšel v časopise

PLOS Genetics


2020 Číslo 7

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se