Drosophila miR-87 promotes dendrite regeneration by targeting the transcriptional repressor Tramtrack69

Autoři: Yasuko Kitatani aff001;  Akane Tezuka aff001;  Eri Hasegawa aff001;  Satoyoshi Yanagi aff001;  Kazuya Togashi aff001;  Masato Tsuji aff001;  Shu Kondo aff002;  Jay Z. Parrish aff003;  Kazuo Emoto aff001
Působiště autorů: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan aff001;  Genetic Strains Research Center, National Institute of Genetics, Yata, Mishima, Shizuoka, Japan aff002;  Department of Biology, University of Washington, Seattle, Washington, United States of America aff003;  International Research Center for Neurointelligence (WPI-IRCN), University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan aff004
Vyšlo v časopise: Drosophila miR-87 promotes dendrite regeneration by targeting the transcriptional repressor Tramtrack69. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008942
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008942


To remodel functional neuronal connectivity, neurons often alter dendrite arbors through elimination and subsequent regeneration of dendritic branches. However, the intrinsic mechanisms underlying this developmentally programmed dendrite regeneration and whether it shares common machinery with injury-induced regeneration remain largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons regenerate adult-specific dendrites after eliminating larval dendrites during metamorphosis. Here we show that the microRNA miR-87 is a critical regulator of dendrite regeneration in Drosophila. miR-87 knockout impairs dendrite regeneration after developmentally-programmed pruning, whereas miR-87 overexpression in C4da neurons leads to precocious initiation of dendrite regeneration. Genetic analyses indicate that the transcriptional repressor Tramtrack69 (Ttk69) is a functional target for miR-87-mediated repression as ttk69 expression is increased in miR-87 knockout neurons and reducing ttk69 expression restores dendrite regeneration to mutants lacking miR-87 function. We further show that miR-87 is required for dendrite regeneration after acute injury in the larval stage, providing a mechanistic link between developmentally programmed and injury-induced dendrite regeneration. These findings thus indicate that miR-87 promotes dendrite regrowth during regeneration at least in part through suppressing Ttk69 in Drosophila sensory neurons and suggest that developmental and injury-induced dendrite regeneration share a common intrinsic mechanism to reactivate dendrite growth.

Klíčová slova:

Developmental neuroscience – Larvae – MicroRNAs – Neuronal dendrites – Neurons – Sensory perception – Nerve regeneration – Regeneration


1. Takeo YH, Kakegawa W, Miura E, Yuzaki M (2015) RORα regulates multiple aspects of dendrite development in cerebellar Purkinje cells in vivo. J Neurosci 35: 12518–12534. doi: 10.1523/JNEUROSCI.0075-15.2015 26354918

2. Mizuno H, et al. (2014) NMDA-regulated dynamics of layer 4 neuronal dendrites during thalamocortical reorganization in neonates. Neuron 82: 365–379. doi: 10.1016/j.neuron.2014.02.026 24685175

3. Nakazawa S, Mizuno H, Iwasato T (2018) Different dynamics of cortical neuron dendrite trees revealed by long-term in vivo imaging in neonates. Nat Commun 9: 3106. doi: 10.1038/s41467-018-05563-0 30082783

4. Emoto K, Parrish JZ, Jan LY, Jan YN (2006) The tumour suppressor Hippo acts with the NDR kinases in dendrite tiling and maintenance. Nature 443: 210–213. doi: 10.1038/nature05090 16906135

5. Parrish JZ, Emoto K, Jan LY, Jan YN (2007) Polycomb genes interact with the tumor suppressor genes hippo and warts in the maintenance of Drosophila sensory neuron dendrites. Genes Dev 21: 956–972. doi: 10.1101/gad.1514507 17437999

6. Koleske AJ. (2013) Molecular mechanisms of dendrite stability. Nat Rev Neurosci 14: 536–550. doi: 10.1038/nrn3486 23839597

7. Murphy TH, Corbett D (2009) Plasticity during stroke recovery: from synapse to behavior. Nat Rev Neurosci 10: 861–872. doi: 10.1038/nrn2735 19888284

8. Ruan YWR, et al. (2006) Dendritic plasticity of CA1 pyramidal neurons after transient grobal ischemia. Neuroscience 140: 191–201. doi: 10.1016/j.neuroscience.2006.01.039 16529877

9. Spigelman I, Yan XX, Obenaus A, Lee EY, Wasterlain CG, Ribak CE (1998) Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy. Neuroscience 86: 109–120. doi: 10.1016/s0306-4522(98)00028-1 9692747

10. Jan YN, Jan LY (2010) Branching out: mechanisms of dendrite arborization. Nat Rev Neurosci 11: 316–328. doi: 10.1038/nrn2836 20404840

11. Yu F, Schuldiner O (2014) Axon and dendrite pruning in Drosophila. Curr Opin Neurobiol 27: 192–198. doi: 10.1016/j.conb.2014.04.005 24793180

12. Kanamori T, Togashi K, Koizumi H, Emoto K (2015) Dendrite remodeling: lessons from invertebrate models. Int Rev Cell Mol Biol 318: 1–15. doi: 10.1016/bs.ircmb.2015.05.001 26315882

13. Kuo CT, Jan LY, Jan YN (2005) Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling. Proc Natl Acad Sci USA 102: 15230–15235. doi: 10.1073/pnas.0507393102 16210248

14. Williams DW, Truman JW (2005) Remodeling dendrites during insect metamorphosis. J Neurobiol 64: 24–33. doi: 10.1002/neu.20151 15884009

15. Kanamori T, Kanai MI, Dairyo Y, Yasunaga KI, Morikawa RK, Emoto K (2013) Compartmentalized calcium transients trigger dendrite pruning in Drosophila sensory neurons. Science 340: 1475–1478. doi: 10.1126/science.1234879 23722427

16. Shimono K, et al. (2009) Multidendritic sensory neurons in the adult Drosophila abdomen: origin, dendritic morphology, and segment- and age-dependent programmed cell death. Neural Dev 4: 37. doi: 10.1186/1749-8104-4-37 19799768

17. Yasunaga KI, Kanamori T, Morikawa R, Emoto K (2010) Dendrite reshaping of adult Drosophila sensory neurons requires matrix metalloproteinase- mediated modification of the basement membranes. Dev Cell 18: 621–632. doi: 10.1016/j.devcel.2010.02.010 20412776

18. Yasunaga KI, et al. (2015) Adult Drosophila sensory neurons specify dendritic territories independently of dendritic contacts through the Wnt5-Drl signaling pathway. Genes Dev 29: 1763–1775. doi: 10.1101/gad.262592.115 26302791

19. Lyons GR, Anderson RO, Abdi K, Song WS, Kuo CT (2014) Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron. Cell Rep 6: 783–791. doi: 10.1016/j.celrep.2014.02.003 24582961

20. Song Y, Ori-McKenney KM, Zheng Y, Han C, Jan LY, Jan YN (2012) Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the AKT pathway involving Pten and microRNA bantam. Genes Dev 26: 1612–1625. doi: 10.1101/gad.193243.112 22759636

21. Stone MC, Albertson RM, Chen L, Rolls MM (2014) Dendrite injury triggers DLK-independent regeneration. Cell Rep 6: 247–253. doi: 10.1016/j.celrep.2013.12.022 24412365

22. Thompson-Peer K, DeVault L, Li T, Jan LY, Jan YN (2016) In vivo dendrite regeneration after injury is different from dendrite development. Genes Dev 30: 1776–1789. doi: 10.1101/gad.282848.116 27542831

23. Devaut L, Li T, Izabel S, Thompson-Peer K, Jan LY, Jan YN (2018) Dendrite regeneration of adult Drosophila sensory neurons diminishes with aging and is inhibited by epidermal-derived matrix metalloproteinase 2. Genes Dev 32: 402–414. doi: 10.1101/gad.308270.117 29563183

24. Chang S, Johnstone RJ, Frokjer-Jensen C, Lockery S, Hobert O (2004) MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 430: 785–789. doi: 10.1038/nature02752 15306811

25. Zou Y, Chiu H, Domenger D, Chuang CF, Chang C (2012) The lin-4 microRNA targets the LIN-14 transcription factor to inhibit Netrin-mediated axon attraction. Sci Signal 5: ra43. doi: 10.1126/scisignal.2002437 22692424

26. Sun AX, Crabtree GR, Yoo AS (2013) MicroRNAs: regulations of neuronal fate. Curr Opin Cell Biol 25: 215–221. doi: 10.1016/j.ceb.2012.12.007 23374323

27. Shenoy A, Blelloch RH (2014) Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat Rev Mol Cell Biol 15: 565–576. doi: 10.1038/nrm3854 25118717

28. Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466: 835–840. doi: 10.1038/nature09267 20703300

29. Djuranovic S, Nahvi A, Green R (2012) miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 336: 237–240. doi: 10.1126/science.1215691 22499947

30. Ghibaudi M, Boido M, Vercelli A (2017) Functional integration of complex miRNA networks in central and peripheral lesion and axonal regeneration. Prog Neurobiol 158: 69–93. doi: 10.1016/j.pneurobio.2017.07.005 28779869

31. Mahar M, Cavalli V (2018) Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci 19: 323–337. doi: 10.1038/s41583-018-0001-8 29666508

32. Gaudet AD, et al. (2016) miR-155 deletion in mice overcomes neuron-intrinsic and neuron-extrinsic barriers to spinal cord repair. J Neurosci 36: 8516–8532. doi: 10.1523/JNEUROSCI.0735-16.2016 27511021

33. Hu YW, Jiang JJ, Gao Y, Wang RY, Tu GJ (2016) MicroRNA-210 promotes sensory axon regeneration of adult mice in vivo and in vitro. Neurosci Lett 622: 61–66. doi: 10.1016/j.neulet.2016.04.034 27102143

34. Yu YM, et al. (2011) MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur J Neurosci 33: 1587–1597 (2011). doi: 10.1111/j.1460-9568.2011.07643.x 21447094

35. Liu CM, Wang RY, Saijilafu, Jiao ZX, Zhang BY, Zhou FQ(2013) MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration. Genes Dev 27: 1473–1483. doi: 10.1101/gad.209619.112 23796896

36. Chen YW, et al. (2014) Systematic study of Drosophila microRNA functions using a collection of targeted knockout mutations. Dev Cell 31: 784–800. doi: 10.1016/j.devcel.2014.11.029 25535920

37. Kanamori T, Yoshino J, Yasunaga KI, Dairyo Y, Emoto K (2015) Local endocytosis triggers dendritic thinning and pruning in Drosophila sensory neurons. Nat Commun 6: 6515. doi: 10.1038/ncomms7515 25761586

38. Parrish JZ, Xu P, Kim CC, Jan LY, Jan YN (2009) The microRNA bantam functions in epithelial cells to regulate scaling growth of dendrite arbors in Drosophila sensory neurons. Neuron 63: 788–802. doi: 10.1016/j.neuron.2009.08.006 19778508

39. Lee T, Luo L (1999) Mosaic analysis with repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22: 451–461. doi: 10.1016/s0896-6273(00)80701-1 10197526

40. Sempere LF, Sokol NS, Dubrosky EB, Berger EM, Ambros V (2003) Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity. Dev Biol 259: 9–18. doi: 10.1016/s0012-1606(03)00208-2 12812784

41. Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113: 25–36. doi: 10.1016/s0092-8674(03)00231-9 12679032

42. Stark A, Brennecke J, Russell RB, Cohen SM (2003) Identification of Drosophila MicroRNA targets. PLoS Biol 1: E60. doi: 10.1371/journal.pbio.0000060 14691535

43. Huang YC, Smith L, Poulton J, Deng WM (2013) The microRNA miR-7 regulates Tramtrack69 in a developmental switch in Drosophila follicle cells. Development 140: 897–905. doi: 10.1242/dev.080192 23325762

44. Xiong WC, Montell C (1993) tramtrack is a transcriptional repressor required for cell fate determination in the Drosophila eye. Genes Dev 7: 1085–1096. doi: 10.1101/gad.7.6.1085 8504931

45. Guo M, Bier E, Jan LY, Jan YN (1995) tramtrack acts downstream of numb to specify distinct daughter cell fates during asymmetric cell divisions in the Drosophila PNS. Neuron 14: 913–925. doi: 10.1016/0896-6273(95)90330-5 7748559

46. Li S, Li Y, Carthew RW, Lai ZC (1997) Photoreceptor cell differentiation requires regulated proteolysis of the transcriptional repressor Tramtrack. Cell 90: 469–478. doi: 10.1016/s0092-8674(00)80507-3 9267027

47. Lai ZC, Li Y (1999) Tramtrack69 is positively and autonomously required for Drosophila photoreceptor development. Genetics 152: 299–305. 10224262

48. Parrish JZ, Kim MD, Jan LY, Jan YN (2006) Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev 20: 820–835. doi: 10.1101/gad.1391006 16547170

49. Kniss JS, Holbrook S, Mergman TG (2013) R7 photoreceptor axon growth is temporally controlled by the transcription factor Ttk69, which inhibits growth in part by promoting transforming growth factor-β/activin signaling. J Neurosci 33: 1509–1520. doi: 10.1523/JNEUROSCI.2023-12.2013 23345225

50. Feoktistov AI, Herman TG (2016) Wallenda/DLK protein levels are temporally downregulated by Tramtrack69 to allow R7 growth cones to become stationary boutons. Development 143: 2983–2993. doi: 10.1242/dev.134403 27402706

51. Iovino N, Pane A, Gaul U (2009) miR-184 has multiple roles in Drosophila female germline development. Dev Cell 17: 123–133. doi: 10.1016/j.devcel.2009.06.008 19619497

52. Cicek IO, Karaca S, Brankatschk M, Eaton S, Urlaub H, Shcherbata HR (2016) Hedgehog signaling strength is orchestrated by the mir-310 cluster of microRNAs in response to diet. Genetics 202: 1167–1183. doi: 10.1534/genetics.115.185371 26801178

53. Yamanaka N, Rewitz KF, O’Connor MB (2013) Ecdysone control of developmental transition: lessons from Drosophila research. Annu Rev Entomol 58: 497–516. doi: 10.1146/annurev-ento-120811-153608 23072462

54. Handler AM (1982) Ecdysteroid titers during pupal and adult development in Drosophila melanogaster. Dev Biol 93: 73–82. doi: 10.1016/0012-1606(82)90240-8 6813165

55. Thummel CS (2001) Molecular mechanisms of developmental timing in C. elegans and Drosophila. Dev Cell 4: 453–465.

56. Cherbas L, Willingham A, Zhag D, Yang L, Zou Y, Eads BD, Carlson JW, Landolin JM, Kapranov P, Dumais J, Samsonova A, Choi JH, Roberts J, Davis C, Tang H, van Baren MJ, Ghosh S, Dobin A, Bell K, Lin W, Langton L, Duff MO, Tenney AE, Zaleski C, Brent MR, Hoskins RA, Kaufman TC, Andrews J, Gravely BR, Perrimon N, Celniker SE, Ginveras TR, and Cherbas P (2011) The transcriptional diversity of 25 Drosophila cell lines. Genome Res 2: 301–314.

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