#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Htt is a repressor of Abl activity required for APP-induced axonal growth


Autoři: Claire Marquilly aff001;  Germain U. Busto aff001;  Brittany S. Leger aff002;  Ana Boulanger aff001;  Edward Giniger aff003;  James A. Walker aff002;  Lee G. Fradkin aff006;  Jean-Maurice Dura aff001
Působiště autorů: IGH, Centre National de la Recherche Scientifique, Univ Montpellier, Montpellier, France aff001;  Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America aff002;  Intramural Research Program, NINDS, NIH, Bethesda, Maryland, United States of America aff003;  Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff004;  Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America aff005;  Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America aff006
Vyšlo v časopise: Htt is a repressor of Abl activity required for APP-induced axonal growth. PLoS Genet 17(1): e1009287. doi:10.1371/journal.pgen.1009287
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009287

Souhrn

Huntington’s disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer’s disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.

Klíčová slova:

Axons – Cloning – Drosophila melanogaster – Fluorescence resonance energy transfer – Hyperexpression techniques – Larvae – Neurons – Phenotypes


Zdroje

1. Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018;21(10):1332–40. Epub 2018/09/27. doi: 10.1038/s41593-018-0235-9 30250260

2. Dugger BN, Dickson DW. Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017;9(7). Epub 2017/01/08. doi: 10.1101/cshperspect.a028035 28062563.

3. Arneson D, Zhang Y, Yang X, Narayanan M. Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks. J Genet. 2018;97(3):795–806. Epub 2018/07/22. 30027910.

4. Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci. 2005;6(12):919–30. Epub 2005/11/17. doi: 10.1038/nrn1806 16288298.

5. Soldano A, Okray Z, Janovska P, Tmejova K, Reynaud E, Claeys A, et al. The Drosophila Homologue of the Amyloid Precursor Protein Is a Conserved Modulator of Wnt PCP Signaling. PLoS biology. 2013;11(5):e1001562. Epub 2013/05/22. doi: 10.1371/journal.pbio.1001562 23690751.

6. Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006;127(4):697–708. Epub 2006/11/18. doi: 10.1016/j.cell.2006.09.036 17110330.

7. Bothwell M, Giniger E. Alzheimer’s disease: neurodevelopment converges with neurodegeneration. Cell. 2000;102(3):271–3. Epub 2000/09/07. doi: 10.1016/s0092-8674(00)00032-5 10975517.

8. Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, et al. Huntington’s disease alters human neurodevelopment. Science. 2020. Epub 2020/07/18. doi: 10.1126/science.aax3338 32675289.

9. Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016;89(5):910–26. Epub 2016/03/05. doi: 10.1016/j.neuron.2016.02.003 26938440.

10. Arribat Y, Bonneaud N, Talmat-Amar Y, Layalle S, Parmentier ML, Maschat F. A huntingtin peptide inhibits polyQ-huntingtin associated defects. PLoS One. 2013;8(7):e68775. Epub 2013/07/19. doi: 10.1371/journal.pone.0068775 23861941.

11. Pouladi MA, Morton AJ, Hayden MR. Choosing an animal model for the study of Huntington’s disease. Nat Rev Neurosci. 2013;14(10):708–21. Epub 2013/09/21. doi: 10.1038/nrn3570 24052178.

12. Zhang S, Feany MB, Saraswati S, Littleton JT, Perrimon N. Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model. Dis Model Mech. 2009;2(5–6):247–66. Epub 2009/04/22. doi: 10.1242/dmm.000653 19380309.

13. Dietz KN, Di Stefano L, Maher RC, Zhu H, Macdonald ME, Gusella JF, et al. The Drosophila Huntington’s disease gene ortholog dhtt influences chromatin regulation during development. Hum Mol Genet. 2015;24(2):330–45. Epub 2014/08/30. doi: 10.1093/hmg/ddu446 25168387.

14. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(9):1423–4. Epub 2019/08/17. doi: 10.1038/s41588-019-0495-7 31417202.

15. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30. Epub 2019/03/02. doi: 10.1038/s41588-019-0358-2 30820047.

16. Bellenguez C, Grenier-Boley B, Lambert JC. Genetics of Alzheimer’s disease: where we are, and where we are going. Curr Opin Neurobiol. 2020;61:40–8. Epub 2019/12/22. doi: 10.1016/j.conb.2019.11.024 31863938.

17. Mlodzik M. The Dishevelled Protein Family: Still Rather a Mystery After Over 20 Years of Molecular Studies. Curr Top Dev Biol. 2016;117:75–91. Epub 2016/03/13. doi: 10.1016/bs.ctdb.2015.11.027 26969973.

18. Sharma M, Castro-Piedras I, Simmons GE Jr., Pruitt K. Dishevelled: A masterful conductor of complex Wnt signals. Cell Signal. 2018;47:52–64. Epub 2018/03/22. doi: 10.1016/j.cellsig.2018.03.004 29559363.

19. Singh J, Yanfeng WA, Grumolato L, Aaronson SA, Mlodzik M. Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation. Genes Dev. 2010;24(19):2157–68. Epub 2010/09/15. doi: 10.1101/gad.1961010 20837657.

20. Colicelli J. ABL tyrosine kinases: Evolution of function, regulation, and specificity. Sci Signal. 2010;3(139):re6. doi: 10.1126/scisignal.3139re6 20841568

21. Wang JYJ. The capable ABL: what is its biological function? Mol Cell Biol. 2014;34(7). doi: 10.1128/MCB.01454-13 24421390

22. Barila D, Superti-Furga G. An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet. 1998;18(3):280–2. Epub 1998/03/21. doi: 10.1038/ng0398-280 9500553.

23. Wen ST, Van Etten RA. The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity. Genes Dev. 1997;11(19):2456–67. Epub 1997/10/23. doi: 10.1101/gad.11.19.2456 9334312.

24. Brasher BB, Van Etten RA. c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. J Biol Chem. 2000;275(45):35631–7. Epub 2000/08/31. 10964922.

25. Schlatterer SD, Acker CM, Davies P. c-Abl in neurodegenerative disease. J Mol Neurosci. 2011;45(3):445–52. Epub 2011/07/06. doi: 10.1007/s12031-011-9588-1 21728062.

26. Fogerty FJ, Juang JL, Petersen J, Clark MJ, Hoffmann FM, Mosher DF. Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis. Oncogene. 1999;18(1):219–32. Epub 1999/02/02. doi: 10.1038/sj.onc.1202239 9926937.

27. Li W, Li Y, Gao FB. Abelson, enabled, and p120 catenin exert distinct effects on dendritic morphogenesis in Drosophila. Dev Dyn. 2005;234(3):512–22. Epub 2005/07/09. doi: 10.1002/dvdy.20496 16003769.

28. Xiong W, Rebay I. Abelson tyrosine kinase is required for Drosophila photoreceptor morphogenesis and retinal epithelial patterning. Dev Dyn. 2011;240(7):1745–55. Epub 2011/06/16. doi: 10.1002/dvdy.22674 21674685.

29. Wills Z, Bateman J, Korey CA, Comer A, Van Vactor D. The tyrosine kinase Abl and its substrate enabled collaborate with the receptor phosphatase Dlar to control motor axon guidance. Neuron. 1999;22(2):301–12. Epub 1999/03/09. doi: 10.1016/s0896-6273(00)81091-0 10069336.

30. Wills Z, Marr L, Zinn K, Goodman CS, Van Vactor D. Profilin and the Abl tyrosine kinase are required for motor axon outgrowth in the Drosophila embryo. Neuron. 1999;22(2):291–9. Epub 1999/03/09. doi: 10.1016/s0896-6273(00)81090-9 10069335.

31. Crowner D, Le Gall M, Gates MA, Giniger E. Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway. Curr Biol. 2003;13(11):967–72. Epub 2003/06/05. doi: 10.1016/s0960-9822(03)00325-7 12781136.

32. Clarke A, McQueen PG, Fang HY, Kannan R, Wang V, McCreedy E, et al. Dynamic morphogenesis of a pioneer axon in Drosophila and its regulation by Abl tyrosine kinase. Mol Biol Cell. 2020;31(6):452–65. Epub 2020/01/23. doi: 10.1091/mbc.E19-10-0563 31967935.

33. Clarke A, McQueen PG, Fang HY, Kannan R, Wang V, McCreedy E, et al. Abl signaling directs growth of a pioneer axon in Drosophila by shaping the intrinsic fluctuations of actin. Mol Biol Cell. 2020;31(6):466–77. Epub 2020/01/23. doi: 10.1091/mbc.E19-10-0564 31967946.

34. Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA. Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J. 2005;24(16):2944–55. Epub 2005/07/30. doi: 10.1038/sj.emboj.7600757 16052209.

35. Busto GU, Cervantes-Sandoval I, Davis RL. Olfactory learning in Drosophila. Physiology (Bethesda). 2010;25(6):338–46. Epub 2010/12/28. doi: 10.1152/physiol.00026.2010 21186278.

36. Heisenberg M. Mushroom body memoir: from maps to models. Nat Rev Neurosci. 2003;4(4):266–75. doi: 10.1038/nrn1074 12671643.

37. Lee T, Lee A, Luo L. Development of the Drosophila mushroom bodies: sequential generation of three distinct types of neurons from a neuroblast. Development. 1999;126(18):4065–76. 10457015.

38. Ng J. Wnt/PCP proteins regulate stereotyped axon branch extension in Drosophila. Development. 2012;139(1):165–77. Epub 2011/12/08. doi: 10.1242/dev.068668 22147954.

39. Luo L, Tully T, White K. Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron. 1992;9(4):595–605. Epub 1992/10/01. doi: 10.1016/0896-6273(92)90024-8 1389179.

40. Reynaud E, Lahaye LL, Boulanger A, Petrova IM, Marquilly C, Flandre A, et al. Guidance of Drosophila Mushroom Body Axons Depends upon DRL-Wnt Receptor Cleavage in the Brain Dorsomedial Lineage Precursors. Cell Rep. 2015;11(8):1293–304. Epub 2015/05/20. doi: 10.1016/j.celrep.2015.04.035 25981040.

41. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118(2):401–15. 8223268

42. Kannan R, Song JK, Karpova T, Clarke A, Shivalkar M, Wang B, et al. The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. Development. 2017;144(3):487–98. Epub 2017/01/15. doi: 10.1242/dev.143776 28087633.

43. Staropoli JF. Tumorigenesis and neurodegeneration: two sides of the same coin? Bioessays. 2008;30(8):719–27. Epub 2008/07/16. doi: 10.1002/bies.20784 18623069.

44. Thion MS, Humbert S. Cancer: From Wild-Type to Mutant Huntingtin. J Huntingtons Dis. 2018;7(3):201–8. Epub 2018/06/12. doi: 10.3233/JHD-180290 29889077.

45. Bowles KR, Jones L. Kinase signalling in Huntington’s disease. J Huntingtons Dis. 2014;3(2):89–123. Epub 2014/07/27. doi: 10.3233/JHD-140106 25062854.

46. Beckett C, Nalivaeva NN, Belyaev ND, Turner AJ. Nuclear signalling by membrane protein intracellular domains: the AICD enigma. Cell Signal. 2012;24(2):402–9. Epub 2011/10/26. doi: 10.1016/j.cellsig.2011.10.007 22024280.

47. Smith JA, Liebl EC. Identification of the molecular lesions in alleles of the Drosophila Abelson tyrosine kinase. Dros Inf Serv. 2005;88:20–2.

48. Bennett RL, Hoffmann FM. Increased levels of the Drosophila Abelson tyrosine kinase in nerves and muscles: subcellular localization and mutant phenotypes imply a role in cell-cell interactions. Development. 1992;116(4):953–66. Epub 1992/12/01. 1295746.

49. Gunawardena S, Her LS, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron. 2003;40(1):25–40. Epub 2003/10/07. doi: 10.1016/s0896-6273(03)00594-4 14527431.

50. Fox DT, Peifer M. Abelson kinase (Abl) and RhoGEF2 regulate actin organization during cell constriction in Drosophila. Development. 2007;134(3):567–78. Epub 2007/01/05. doi: 10.1242/dev.02748 17202187.

51. Aso Y, Grubel K, Busch S, Friedrich AB, Siwanowicz I, Tanimoto H. The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet. 2009;23(1–2):156–72. Epub 2009/01/14. doi: 10.1080/01677060802471718 19140035.

52. Boulanger A, Clouet-Redt C, Farge M, Flandre A, Guignard T, Fernando C, et al. ftz-f1 and Hr39 opposing roles on EcR expression during Drosophila mushroom body neuron remodeling. Nat Neurosci. 2011;14(1):37–44. Epub 2010/12/07. doi: 10.1038/nn.2700 21131955.

53. Lee T, Luo L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron. 1999;22(3):451–61. doi: 10.1016/s0896-6273(00)80701-1 10197526.

54. Kyriakakis P, Tipping M, Abed L, Veraksa A. Tandem affinity purification in Drosophila: the advantages of the GS-TAP system. Fly (Austin). 2008;2(4):229–35. Epub 2008/08/23. doi: 10.4161/fly.6669 18719405.

55. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5. Epub 2012/08/30. doi: 10.1038/nmeth.2089 22930834.

56. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115. Epub 2012/06/26. doi: 10.1093/nar/gks596 22730293.

57. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. Epub 2002/02/16. doi: 10.1006/meth.2001.1262 11846609.

58. Song JK, Kannan R, Merdes G, Singh J, Mlodzik M, Giniger E. Disabled is a bona fide component of the Abl signaling network. Development. 2010;137(21):3719–27. Epub 2010/10/14. doi: 10.1242/dev.050948 20940230.

59. Ting AY, Kain KH, Klemke RL, Tsien RY. Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells. Proc Natl Acad Sci U S A. 2001;98(26):15003–8. Epub 2001/12/26. doi: 10.1073/pnas.211564598 11752449.


Článek vyšel v časopise

PLOS Genetics


2021 Číslo 1
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Halitóza
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Přihlášení
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

#ADS_BOTTOM_SCRIPTS#