Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control

English version České info

The development of a functional nervous system requires that nerve cells are generated at exactly the right time and place to be correctly integrated. Defects in the timing at which nerve cells are generated, or ‘differentiate’, lead to neurological disorders such as epilepsy and autism. However, very little is known about the identity of the genes that control the timing of nerve cell differentiation. Using developing photoreceptor nerves in the eye of the fruit fly, Drosophila, as a model, we showed previously that a molecular pathway known as ‘mTOR signalling’ is a key regulator of the timing of differentiation. In this study we have identified two new genes, unkempt and headcase, which control the timing of photoreceptor differentiation in Drosophila. The activity of unkempt and headcase is controlled by mTOR signalling and it is through these genes that mTOR is able to control nerve cell differentiation. The proteins encoded by unkempt and headcase form a complex and act synergistically to control the development of Drosophila photoreceptors. mTOR signalling controls a number of important cellular processes, but unkempt and headcase are the first components of this pathway to be identified that control nerve cell differentiation.

Vyšlo v časopise: Unkempt Is Negatively Regulated by mTOR and Uncouples Neuronal Differentiation from Growth Control. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004624
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004624

Souhrn

Zdroje

1. RussellRC, FangC, GuanKL (2011) An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development 138: 3343–3356.

2. WullschlegerS, LoewithR, HallMN (2006) TOR signaling in growth and metabolism. Cell 124: 471–484.

3. ZoncuR, EfeyanA, SabatiniDM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12: 21–35.

4. OrlovaKA, CrinoPB (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184: 87–105.

5. LjungbergMC, BhattacharjeeMB, LuY, ArmstrongDL, YoshorD, et al. (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60: 420–429.

6. RussoE, CitraroR, ConstantiA, De SarroG (2012) The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol Neurobiol 46: 662–681.

7. ZengLH, RensingNR, WongM (2009) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29: 6964–6972.

8. BatemanJM, McNeillH (2004) Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila. Cell 119: 87–96.

9. BatemanJM, McNeillH (2006) Insulin/IGF signalling in neurogenesis. Cell Mol Life Sci 63: 1701–1705.

10. McNeillH, CraigGM, BatemanJM (2008) Regulation of neurogenesis and epidermal growth factor receptor signaling by the insulin receptor/target of rapamycin pathway in Drosophila. Genetics 179: 843–853.

11. HanJ, WangB, XiaoZ, GaoY, ZhaoY, et al. (2008) Mammalian target of rapamycin (mTOR) is involved in the neuronal differentiation of neural progenitors induced by insulin. Mol Cell Neurosci 39: 118–124.

12. OtaegiG, Yusta-BoyoMJ, Vergano-VeraE, Mendez-GomezHR, CarreraAC, et al. (2006) Modulation of the PI 3-kinase-Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells. J Cell Sci 119: 2739–2748.

13. FishwickKJ, LiRA, HalleyP, DengP, StoreyKG (2010) Initiation of neuronal differentiation requires PI3-kinase/TOR signalling in the vertebrate neural tube. Dev Biol 338: 215–225.

14. MalageladaC, Lopez-ToledanoMA, WillettRT, JinZH, ShelanskiML, et al. (2011) RTP801/REDD1 regulates the timing of cortical neurogenesis and neuron migration. J Neurosci 31: 3186–3196.

15. FelicianoDM, QuonJL, SuT, TaylorMM, BordeyA (2012) Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion. Hum Mol Genet 21: 799–810.

16. LafourcadeCA, LinTV, FelicianoDM, ZhangL, HsiehLS, et al. (2013) Rheb activation in subventricular zone progenitors leads to heterotopia, ectopic neuronal differentiation, and rapamycin-sensitive olfactory micronodules and dendrite hypertrophy of newborn neurons. J Neurosci 33: 2419–2431.

17. ZhuG, ChowLM, BayazitovIT, TongY, GilbertsonRJ, et al. (2012) Pten deletion causes mTorc1-dependent ectopic neuroblast differentiation without causing uniform migration defects. Development 139: 3422–3431.

18. GuertinDA, GunturKV, BellGW, ThoreenCC, SabatiniDM (2006) Functional genomics identifies TOR-regulated genes that control growth and division. Curr Biol 16: 958–970.

19. WeaverTA, WhiteRA (1995) headcase, an imaginal specific gene required for adult morphogenesis in Drosophila melanogaster. Development 121: 4149–4160.

20. Wolff T, Ready D (1993) Pattern Formation in the Drosophila Retina. In: M B, A M-A, editors. The Development of Drosophila melanogaster: CSHL Press. pp.1277–1326.

21. GlatterT, SchittenhelmRB, RinnerO, RoguskaK, WepfA, et al. (2011) Modularity and hormone sensitivity of the Drosophila melanogaster insulin receptor/target of rapamycin interaction proteome. Mol Syst Biol 7: 547.

22. HsuPP, KangSA, RamesederJ, ZhangY, OttinaKA, et al. (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332: 1317–1322.

23. YuY, YoonSO, PoulogiannisG, YangQ, MaXM, et al. (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332: 1322–1326.

24. MohlerJ, WeissN, MurliS, MohammadiS, VaniK, et al. (1992) The embryonically active gene, unkempt, of Drosophila encodes a Cys3His finger protein. Genetics 131: 377–388.

25. GoberdhanDC, ParicioN, GoodmanEC, MlodzikM, WilsonC (1999) Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev 13: 3244–3258.

26. PinalN, GoberdhanDC, CollinsonL, FujitaY, CoxIM, et al. (2006) Regulated and polarized PtdIns(3, 4, 5)P3 accumulation is essential for apical membrane morphogenesis in photoreceptor epithelial cells. Curr Biol 16: 140–149.

27. HarringtonLS, FindlayGM, GrayA, TolkachevaT, WigfieldS, et al. (2004) The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166: 213–223.

28. GiotL, BaderJS, BrouwerC, ChaudhuriA, KuangB, et al. (2003) A protein interaction map of Drosophila melanogaster. Science 302: 1727–1736.

29. VeraksaA, BauerA, Artavanis-TsakonasS (2005) Analyzing protein complexes in Drosophila with tandem affinity purification-mass spectrometry. Dev Dyn 232: 827–834.

30. StenebergP, SamakovlisC (2001) A novel stop codon readthrough mechanism produces functional Headcase protein in Drosophila trachea. EMBO Rep 2: 593–597.

31. FuW, NollM (1997) The Pax2 homolog sparkling is required for development of cone and pigment cells in the Drosophila eye. Genes Dev 11: 2066–2078.

32. Miyamoto-SatoE, FujimoriS, IshizakaM, HiraiN, MasuokaK, et al. (2010) A comprehensive resource of interacting protein regions for refining human transcription factor networks. PLoS One 5: e9289.

33. HartmanNW, LinTV, ZhangL, PaqueletGE, FelicianoDM, et al. (2013) mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2, to regulate neural stem cell self-renewal in vivo. Cell Rep 5: 433–444.

34. GaoX, PanD (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15: 1383–1392.

35. PotterCJ, HuangH, XuT (2001) Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105: 357–368.

36. StockerH, RadimerskiT, SchindelholzB, WittwerF, BelawatP, et al. (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5: 559–565.

37. TaponN, ItoN, DicksonBJ, TreismanJE, HariharanIK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105: 345–355.

38. FelicianoDM, SuT, LopezJ, PlatelJC, BordeyA (2011) Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J Clin Invest 121: 1596–1607.

39. ShiY, NollM (2009) Determination of cell fates in the R7 equivalence group of the Drosophila eye by the concerted regulation of D-Pax2 and TTK88. Dev Biol 331: 68–77.

40. LoncleN, WilliamsDW (2012) An interaction screen identifies headcase as a regulator of large-scale pruning. J Neurosci 32: 17086–17096.

41. GhabrialAS, LeviBP, KrasnowMA (2011) A systematic screen for tube morphogenesis and branching genes in the Drosophila tracheal system. PLoS Genet 7: e1002087.

42. LoresP, VisvikisO, LunaR, LemichezE, GaconG (2010) The SWI/SNF protein BAF60b is ubiquitinated through a signalling process involving Rac GTPase and the RING finger protein Unkempt. FEBS J 277: 1453–1464.

43. BlackshawS, HarpavatS, TrimarchiJ, CaiL, HuangH, et al. (2004) Genomic analysis of mouse retinal development. PLoS Biol 2: E247.

44. PunzoC, KornackerK, CepkoCL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 12: 44–52.

45. WeiJ, LiP, ChiribogaL, MizuguchiM, YeeH, et al. (2002) Tuberous sclerosis in a 19-week fetus: immunohistochemical and molecular study of hamartin and tuberin. Pediatr Dev Pathol 5: 448–464.

46. WeinkoveD, NeufeldTP, TwardzikT, WaterfieldMD, LeeversSJ (1999) Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adaptor. Curr Biol 9: 1019–1029.

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

48. YangCH, SimonMA, McNeillH (1999) mirror controls planar polarity and equator formation through repression of fringe expression and through control of cell affinities. Development 126: 5857–5866.

49. RobertsonHM, PrestonCR, PhillisRW, Johnson-SchlitzDM, BenzWK, et al. (1988) A stable genomic source of P element transposase in Drosophila melanogaster. Genetics 118: 461–470.

50. ThibaultST, SingerMA, MiyazakiWY, MilashB, DompeNA, et al. (2004) A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat Genet 36: 283–287.

51. KockelL, KerrKS, MelnickM, BrucknerK, HebrokM, et al. (2010) Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling. PLoS Genet 6: e1000990.

52. MachadoP, RostaingP, GuigonisJM, RennerM, DumoulinA, et al. (2011) Heat shock cognate protein 70 regulates gephyrin clustering. J Neurosci 31: 3–14.