COE Loss-of-Function Analysis Reveals a Genetic Program Underlying Maintenance and Regeneration of the Nervous System in Planarians

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COE transcription factors are conserved across widely divergent animals and are crucial for organismal development. COE genes also play roles in adult animals and have been implicated in central nervous system (CNS) diseases; however, the function of COE in the post-embryonic CNS remains poorly understood. Planarian regeneration provides an excellent model to study the function of transcription factors in cell differentiation and in terminally differentiated cells. In planarians, coe is expressed in differentiating and mature neurons, and its function is required for CNS regeneration. In this study, we show that coe is required to maintain structure and function of the CNS in uninjured planarians. We took advantage of this phenotype to identify genes regulated by coe by comparing global gene expression changes between control and coe mRNA-deficient planarians. This approach revealed downregulated genes downstream of coe with biological roles in CNS function. Expression analysis of downregulated genes uncovered previously unknown candidate targets of coe in the CNS. Furthermore, functional analysis of downstream targets identified coe-regulated genes required for CNS regeneration. These results demonstrate that the roles of COE in stem cell specification and neuronal function are active and indispensable during CNS renewal in adult animals.

Vyšlo v časopise: COE Loss-of-Function Analysis Reveals a Genetic Program Underlying Maintenance and Regeneration of the Nervous System in Planarians. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004746
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004746

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1. DaburonV, MellaS, PlouhinecJL, MazanS, CrozatierM, et al. (2008) The metazoan history of the COE transcription factors. Selection of a variant HLH motif by mandatory inclusion of a duplicated exon in vertebrates. BMC Evol Biol 8: 131.

2. DemillyA, SimionatoE, OhayonD, KernerP, GarcesA, et al. (2011) Coe genes are expressed in differentiating neurons in the central nervous system of protostomes. PLoS ONE 6: e21213.

3. JacksonDJ, MeyerNP, SeaverE, PangK, McDougallC, et al. (2010) Developmental expression of COE across the Metazoa supports a conserved role in neuronal cell-type specification and mesodermal development. Dev Genes Evol 220: 221–234.

4. LibergD, SigvardssonM, AkerbladP (2002) The EBF/Olf/Collier family of transcription factors: regulators of differentiation in cells originating from all three embryonal germ layers. Mol Cell Biol 22: 8389–8397.

5. CrozatierM, VincentA (2008) Control of multidendritic neuron differentiation in Drosophila: the role of Collier. Dev Biol 315: 232–242.

6. DuboisL, Bally-CuifL, CrozatierM, MoreauJ, PaquereauL, et al. (1998) XCoe2, a transcription factor of the Col/Olf-1/EBF family involved in the specification of primary neurons in Xenopus. Curr Biol 8: 199–209.

7. GarelS, Garcia-DominguezM, CharnayP (2000) Control of the migratory pathway of facial branchiomotor neurones. Development 127: 5297–5307.

8. Jinushi-NakaoS, ArvindR, AmikuraR, KinameriE, LiuAW, et al. (2007) Knot/Collier and cut control different aspects of dendrite cytoskeleton and synergize to define final arbor shape. Neuron 56: 963–978.

9. PozzoliO, BosettiA, CrociL, ConsalezGG, VetterML (2001) Xebf3 is a regulator of neuronal differentiation during primary neurogenesis in Xenopus. Dev Biol 233: 495–512.

10. PrasadBC, YeB, ZackharyR, SchraderK, SeydouxG, et al. (1998) unc-3, a gene required for axonal guidance in Caenorhabditis elegans, encodes a member of the O/E family of transcription factors. Development 125: 1561–1568.

11. WightmanB, BaranR, GarrigaG (1997) Genes that guide growth cones along the C. elegans ventral nerve cord. Development 124: 2571–2580.

12. KimK, ColosimoME, YeungH, SenguptaP (2005) The UNC-3 Olf/EBF protein represses alternate neuronal programs to specify chemosensory neuron identity. Dev Biol 286: 136–148.

13. HattoriY, UsuiT, SatohD, MoriyamaS, ShimonoK, et al. (2013) Sensory-neuron subtype-specific transcriptional programs controlling dendrite morphogenesis: genome-wide analysis of Abrupt and Knot/Collier. Dev Cell 27: 530–544.

14. KratsiosP, StolfiA, LevineM, HobertO (2012) Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nat Neurosci 15: 205–214.

15. EadeKT, FancherHA, RidyardMS, AllanDW (2012) Developmental transcriptional networks are required to maintain neuronal subtype identity in the mature nervous system. PLoS Genet 8: e1002501.

16. ZhaoLY, NiuY, SantiagoA, LiuJ, AlbertSH, et al. (2006) An EBF3-mediated transcriptional program that induces cell cycle arrest and apoptosis. Cancer Res 66: 9445–9452.

17. LiaoD (2009) Emerging roles of the EBF family of transcription factors in tumor suppression. Mol Cancer Res 7: 1893–1901.

18. MaherEA, BrennanC, WenPY, DursoL, LigonKL, et al. (2006) Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res 66: 11502–11513.

19. MullighanCG, GoorhaS, RadtkeI, MillerCB, Coustan-SmithE, et al. (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446: 758–764.

20. ZardoG, TiirikainenMI, HongC, MisraA, FeuersteinBG, et al. (2002) Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet 32: 453–458.

21. ZhuZ, HuangfuD (2013) Human pluripotent stem cells: an emerging model in developmental biology. Development 140: 705–717.

22. ElliottSA, Sánchez AlvaradoA (2012) The history and enduring contributions of planarians to the study of animal regeneration. WIREs Dev Biol 2012 doi:101002/wdev82

23. WagnerDE, WangIE, ReddienPW (2011) Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science 332: 811–816.

24. CowlesMW, BrownDD, NisperosSV, StanleyBN, PearsonBJ, et al. (2013) Genome-wide analysis of the bHLH gene family in planarians identifies factors required for adult neurogenesis and neuronal regeneration. Development 140: 4691–4702.

25. CurrieKW, PearsonBJ (2013) Transcription factors lhx1/5-1 and pitx are required for the maintenance and regeneration of serotonergic neurons in planarians. Development 140: 3577–3588.

26. LapanSW, ReddienPW (2012) Transcriptome analysis of the planarian eye identifies ovo as a specific regulator of eye regeneration. Cell Rep 2: 294–307.

27. MärzM, SeebeckF, BartschererK (2013) A Pitx transcription factor controls the establishment and maintenance of the serotonergic lineage in planarians. Development 140: 4499–4509.

28. AdlerCE, SeidelCW, McKinneySA, Sanchez AlvaradoA (2014) Selective amputation of the pharynx identifies a FoxA-dependent regeneration program in planaria. Elife 3: e02238.

29. ScimoneML, Kravarik KellieM, Lapan SylvainW, Reddien PeterW (2014) Neoblast Specialization in Regeneration of the Planarian Schmidtea mediterranea. Stem Cell Reports 3: 339–352.

30. CollinsJJ3rd, HouX, RomanovaEV, LambrusBG, MillerCM, et al. (2010) Genome-wide analyses reveal a role for peptide hormones in planarian germline development. PLoS Biol 8: e1000509.

31. GentileL, CebriàF, BartschererK (2011) The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration. Dis Model Mech 4: 12–19.

32. UmesonoY, TasakiJ, NishimuraK, InoueT, AgataK (2011) Regeneration in an evolutionarily primitive brain–the planarian Dugesia japonica model. Eur J Neurosci 34: 863–869.

33. LapanSW, ReddienPW (2011) dlx and sp6-9 Control optic cup regeneration in a prototypic eye. PLoS Genet 7: e1002226.

34. WenemoserD, LapanSW, WilkinsonAW, BellGW, ReddienPW (2012) A molecular wound response program associated with regeneration initiation in planarians. Genes Dev 26: 988–1002.

35. SandmannT, VoggMC, OwlarnS, BoutrosM, BartschererK (2011) The head-regeneration transcriptome of the planarian Schmidtea mediterranea. Genome Biol 12: R76.

36. WenemoserD, ReddienPW (2010) Planarian regeneration involves distinct stem cell responses to wounds and tissue absence. Dev Biol 344: 979–991.

37. WitchleyJN, MayerM, WagnerDE, OwenJH, ReddienPW (2013) Muscle cells provide instructions for planarian regeneration. Cell Rep 4: 633–641.

38. OviedoNJ, NewmarkPA, Sánchez AlvaradoA (2003) Allometric scaling and proportion regulation in the freshwater planarian Schmidtea mediterranea. Dev Dyn 226: 326–333.

39. GreenYS, VetterML (2011) EBF factors drive expression of multiple classes of target genes governing neuronal development. Neural Dev 6: 19.

40. CrozatierM, VincentA (1999) Requirement for the Drosophila COE transcription factor Collier in formation of an embryonic muscle: transcriptional response to notch signalling. Development 126: 1495–1504.

41. CaroleiA, MargottaV, PalladiniG (1975) Proposal of a new model with dopaminergic-cholinergic interactions for neuropharmacological investigations. Neuropsychobiology 1: 355–364.

42. ButtarelliFR, PontieriFE, MargottaV, PalladiniG (2000) Acetylcholine/dopamine interaction in planaria. Comp Biochem Physiol C Toxicol Pharmacol 125: 225–231.

43. NishimuraK, KitamuraY, TaniguchiT, AgataK (2010) Analysis of motor function modulated by cholinergic neurons in planarian Dugesia japonica. Neuroscience 168: 18–30.

44. CebriàF, NewmarkPA (2005) Planarian homologs of netrin and netrin receptor are required for proper regeneration of the central nervous system and the maintenance of nervous system architecture. Development 132: 3691–3703.

45. TsengAS, BeaneWS, LemireJM, MasiA, LevinM (2010) Induction of vertebrate regeneration by a transient sodium current. J Neurosci 30: 13192–13200.

46. BeaneWS, MorokumaJ, AdamsDS, LevinM (2011) A chemical genetics approach reveals H,K-ATPase-mediated membrane voltage is required for planarian head regeneration. Chem Biol 18: 77–89.

47. BeaneWS, MorokumaJ, LemireJM, LevinM (2013) Bioelectric signaling regulates head and organ size during planarian regeneration. Development 140: 313–322.

48. LabbéRM, IrimiaM, CurrieKW, LinA, ZhuSJ, et al. (2012) A Comparative Transcriptomic Analysis Reveals Conserved Features of Stem Cell Pluripotency in Planarians and Mammals. Stem Cells 30: 1734–1745.

49. LatchmanDS (1999) POU family transcription factors in the nervous system. J Cell Physiol 179: 126–133.

50. Urbach R, Technau G (2008) Dorsoventral Patterning of the Brain: A Comparative Approach. In: Technau G, editor. Brain Development in Drosophila melanogaster: Springer New York. pp. 42–56.

51. McMahonAP (2000) Neural patterning: The role of Nkx genes in the ventral spinal cord. Genes Dev 14: 2261–2264.

52. DenerisES, HobertO (2014) Maintenance of postmitotic neuronal cell identity. Nat Neurosci 17: 899–907.

53. GurleyKA, RinkJC, Sánchez AlvaradoA (2008) Beta-catenin defines head versus tail identity during planarian regeneration and homeostasis. Science 319: 323–327.

54. KingRS, NewmarkPA (2013) In situ hybridization protocol for enhanced detection of gene expression in the planarian Schmidtea mediterranea. BMC Dev Biol 13: 8.

55. LauterG, SollI, HauptmannG (2011) Two-color fluorescent in situ hybridization in the embryonic zebrafish brain using differential detection systems. BMC Dev Biol 11: 43.

56. UmesonoY, WatanabeK, AgataK (1997) A planarian orthopedia homolog is specifically expressed in the branch region of both the mature and regenerating brain. Dev Growth Differ 39: 723–727.

57. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25: 1105–1111.

58. AdamidiC, WangY, GruenD, MastrobuoniG, YouX, et al. (2011) De novo assembly and validation of planaria transcriptome by massive parallel sequencing and shotgun proteomics. Genome Res 21: 1193–1200.

59. ÖnalP, GrunD, AdamidiC, RybakA, SolanaJ, et al. (2012) Gene expression of pluripotency determinants is conserved between mammalian and planarian stem cells. EMBO J 31: 2755–2769.

60. RobinsonMD, McCarthyDJ, SmythGK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139–140.

61. DennisGJr, ShermanBT, HosackDA, YangJ, GaoW, et al. (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3.

62. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.

63. ZayasRM, HernándezA, HabermannB, WangY, StaryJM, et al. (2005) The planarian Schmidtea mediterranea as a model for epigenetic germ cell specification: Analysis of ESTs from the hermaphroditic strain. Proc Natl Acad Sci U S A 102: 18491–18496.

64. ReddienPW, BermangeAL, MurfittKJ, JenningsJR, Sánchez AlvaradoA (2005) Identification of genes needed for regeneration, stem cell function, and tissue homeostasis by systematic gene perturbation in planaria. Dev Cell 8: 635–649.

65. SchneiderCA, RasbandWS, EliceiriKW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9: 671–675.