NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

Autoři: Mayanglambam Dhruba Singh aff001;  Matthew Jensen aff001;  Micaela Lasser aff002;  Emily Huber aff001;  Tanzeen Yusuff aff001;  Lucilla Pizzo aff001;  Brian Lifschutz aff001;  Inshya Desai aff001;  Alexis Kubina aff001;  Sneha Yennawar aff001;  Sydney Kim aff002;  Janani Iyer aff001;  Diego E. Rincon-Limas aff003;  Laura Anne Lowery aff002;  Santhosh Girirajan aff001
Působiště autorů: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff001;  Department of Biology, Boston College, Chestnut Hill, Massachusetts, United States of America aff002;  Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America aff003;  Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff004;  Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States of America aff004;  Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff005
Vyšlo v časopise: NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008590
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008590


The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.

Klíčová slova:

Apoptosis – Cell staining – Drosophila melanogaster – Eyes – Hyperexpression techniques – Phenotypes – RNA interference – Xenopus


1. Malhotra D, Sebat J. CNVs: Harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148: 1223–1241. doi: 10.1016/j.cell.2012.02.039 22424231

2. Girirajan S, Campbell CD, Eichler EE. Human Copy Number Variation and Complex Genetic Disease. Annu Rev Genet. 2011;45: 203–226. doi: 10.1146/annurev-genet-102209-163544 21854229

3. Girirajan S, Eichler EE. Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet. 2010;19: R176–87. doi: 10.1093/hmg/ddq366 20807775

4. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A. 1995;92: 7612–7616. doi: 10.1073/pnas.92.17.7612 7644464

5. Karayiorgou M, Simon TJ, Gogos JA. 22q11.2 microdeletions: Linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci. 2010;11: 402–416. doi: 10.1038/nrn2841 20485365

6. Fenelon K, Mukai J, Xu B, Hsu P-K, Drew LJ, Karayiorgou M, et al. Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc Natl Acad Sci U S A. 2011;108: 4447–4452. doi: 10.1073/pnas.1101219108 21368174

7. Mukai J, Tamura M, Fénelon K, Rosen AM, Spellman TJ, Kang R, et al. Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron. 2015;86: 680–95. doi: 10.1016/j.neuron.2015.04.003 25913858

8. Ballif BC, Theisen A, Coppinger J, Gowans GC, Hersh JH, Madan-Khetarpal S, et al. Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet. 2008;1: 8. doi: 10.1186/1755-8166-1-8 18471269

9. Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010;87: 229–236. doi: 10.1016/j.ajhg.2010.07.013 20691406

10. Glassford MR, Rosenfeld JA, Freedman AA, Zwick ME, Mulle JG. Novel features of 3q29 deletion syndrome: Results from the 3q29 registry. Am J Med Genet Part A. 2016;170: 999–1006. doi: 10.1002/ajmg.a.37537 26738761

11. Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17: 142–153. doi: 10.1038/mp.2011.154 22083728

12. Mulle JG. The 3q29 deletion confers >40-fold increase in risk for schizophrenia. Mol Psychiatry. 2015;20: 1028–1029. doi: 10.1038/mp.2015.76 26055425

13. Pollak RM, Murphy MM, Epstein MP, Zwick ME, Klaiman C, Saulnier CA, et al. Neuropsychiatric phenotypes and a distinct constellation of ASD features in 3q29 deletion syndrome: results from the 3q29 registry. Mol Autism. 2019;10: 30. doi: 10.1186/s13229-019-0281-5 31346402

14. Rutkowski TP, Purcell RH, Pollak RM, Grewenow SM, Gafford GM, Malone T, et al. Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion. Mol Psychiatry. 2019. doi: 10.1038/s41380-019-0413-5 30976085

15. Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, et al. Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. Neuropsychopharmacology. 2019;44: 2125–2135. doi: 10.1038/s41386-019-0441-5 31216562

16. Quintero-Rivera F, Sharifi-Hannauer P, Martinez-Agosto JA. Autistic and psychiatric findings associated with the 3q29 microdeletion syndrome: Case report and review. Am J Med Genet Part A. 2010;152 A: 2459–2467. doi: 10.1002/ajmg.a.33573 20830797

17. Rutkowski TP, Schroeder JP, Gafford GM, Warren ST, Weinshenker D, Caspary T, et al. Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders. J Neurosci Res. 2017;95: 1144–1160. doi: 10.1002/jnr.23970 27859486

18. Budnik V, Koh YH, Guan B, Hartmann B, Hough C, Woods D, et al. Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg. Neuron. 1996;17: 627–640. doi: 10.1016/s0896-6273(00)80196-8 8893021

19. Walch L. Emerging role of the scaffolding protein Dlg1 in vesicle trafficking. Traffic. 2013;14: 964–973. doi: 10.1111/tra.12089 23829493

20. Andrews T, Meader S, Vulto-van Silfhout A, Taylor A, Steinberg J, Hehir-Kwa J, et al. Gene Networks Underlying Convergent and Pleiotropic Phenotypes in a Large and Systematically-Phenotyped Cohort with Heterogeneous Developmental Disorders. PLoS Genet. 2015;11: e1005012. doi: 10.1371/journal.pgen.1005012 25781962

21. Iyer J, Singh MD, Jensen M, Patel P, Pizzo L, Huber E, et al. Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster. Nat Commun. 2018;9: 2548. doi: 10.1038/s41467-018-04882-6 29959322

22. Jensen M, Girirajan S. An interaction-based model for neuropsychiatric features of copy-number variants. PLoS Genet. 2019;15: e1007879. doi: 10.1371/journal.pgen.1007879 30653500

23. Wangler MF, Yamamoto S, Bellen HJ. Fruit flies in biomedical research. Genetics. 2015;199: 639–653. doi: 10.1534/genetics.114.171785 25624315

24. Pratt KG, Khakhalin AS. Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets. Dis Model Mech. 2013;6: 1057–1065. doi: 10.1242/dmm.012138 23929939

25. Reiter LT, Potocki L, Chien S, Gribskov M, Bier E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 2001;11: 1114–1125. doi: 10.1101/gr.169101 11381037

26. Gatto CL, Broadie K. Drosophila modeling of heritable neurodevelopmental disorders. Curr Opin Neurobiol. 2011;21: 834–841. doi: 10.1016/j.conb.2011.04.009 21596554

27. Harland RM, Grainger RM. Xenopus research: Metamorphosed by genetics and genomics. Trends Genet. 2011;27: 507–515. doi: 10.1016/j.tig.2011.08.003 21963197

28. Dickman DK, Davis GW. The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science. 2009;326: 1127–1130. doi: 10.1126/science.1179685 19965435

29. Shao L, Shuai Y, Wang J, Feng S, Lu B, Li Z, et al. Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila. Proc Natl Acad Sci U S A. 2011;108: 18831–18836. doi: 10.1073/pnas.1114569108 22049342

30. Wu Y, Bolduc F V., Bell K, Tully T, Fang Y, Sehgal A, et al. A Drosophila model for Angelman syndrome. Proc Natl Acad Sci U S A. 2008;105: 12399–12404. doi: 10.1073/pnas.0805291105 18701717

31. Marshak S, Meynard MM, de Vries YA, Kidane AH, Cohen-Cory S. Cell-autonomous alterations in dendritic arbor morphology and connectivity induced by overexpression of MeCP2 in Xenopus central neurons in vivo. PLoS One. 2012;7: e33153. doi: 10.1371/journal.pone.0033153 22427975

32. Muller BM, Kistner U, Veh RW, Cases-Langhoff C, Becker B, Gundelfinger ED, et al. Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein. J Neurosci. 1995;15: 2354–2366. doi: 10.1523/JNEUROSCI.15-03-02354.1995 7891172

33. Sabin LR, Zhou R, Gruber JJ, Lukinova N, Bambina S, Berman A, et al. Ars2 Regulates Both miRNA- and siRNA- Dependent Silencing and Suppresses RNA Virus Infection in Drosophila. Cell. 2009;138: 340–351. doi: 10.1016/j.cell.2009.04.045 19632183

34. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118: 401–415. 8223268

35. Thomas U, Kim E, Kuhlendahl S, Koh YH, Gundelfinger ED, Sheng M, et al. Synaptic clustering of the cell adhesion molecule Fasciclin II by discs- large and its role in the regulation of presynaptic structure. Neuron. 1997;19: 787–799. doi: 10.1016/s0896-6273(00)80961-7 9354326

36. Armstrong JD, Texada MJ, Munjaal R, Baker DA, Beckingham KM. Gravitaxis in Drosophila melanogaster: A forward genetic screen. Genes, Brain Behav. 2006;5: 222–239. doi: 10.1111/j.1601-183X.2005.00154.x 16594976

37. Mendoza-Topaz C, Urra F, Barría R, Albornoz V, Ugalde D, Thomas U, et al. DLGS97/SAP97 is developmentally upregulated and is required for complex adult behaviors and synapse morphology and function. J Neurosci. 2008;28: 304–314. doi: 10.1523/JNEUROSCI.4395-07.2008 18171947

38. Hing H, Xiao J, Harden N, Lim L, Lawrence Zipursky S. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila. Cell. 1999;97: 853–863. doi: 10.1016/s0092-8674(00)80798-9 10399914

39. Kim MD, Kamiyama D, Kolodziej P, Hing H, Chiba A. Isolation of Rho GTPase effector pathways during axon development. Dev Biol. 2003;262: 282–293. doi: 10.1016/s0012-1606(03)00393-2 14550791

40. Parnas D, Haghighi AP, Fetter RD, Kim SW, Goodman CS. Regulation of postsynaptic structure and protein localization by the Rho-type guanine nucleotide exchange factor dPix. Neuron. 2001;32: 415–424. doi: 10.1016/s0896-6273(01)00485-8 11709153

41. Ng J, Luo L. Rho GTPases regulate axon growth through convergent and divergent signaling pathways. Neuron. 2004;44: 779–793. doi: 10.1016/j.neuron.2004.11.014 15572110

42. Sherwood NT, Sun Q, Xue M, Zhang B, Zinn K. Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol. 2004;2: e429. doi: 10.1371/journal.pbio.0020429 15562320

43. Chen SY, Huang PH, Cheng HJ. Disrupted-in-schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci U S A. 2011;108: 5861–5866. doi: 10.1073/pnas.1018128108 21422296

44. Morales J, Hiesinger PR, Schroeder AJ, Kume K, Verstreken P, Jackson FR, et al. Drosophila fragile X protein DFXR regulates neuronal morphology and function in the brain. Neuron. 2002;34: 961–972. doi: 10.1016/s0896-6273(02)00731-6 12086643

45. Thomas BJ, Wassarman DA. A fly’s eye view of biology. Trends Genet. 1999;15: 184–190. doi: 10.1016/s0168-9525(99)01720-5 10322485

46. Thaker HM, Kankel DR. Mosaic analysis gives an estimate of the extent of genomic involvement in the development of the visual system in Drosophila melanogaster. Genetics. 1992;131: 883–894. 1516819

47. Oortveld MAW, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, Kochinke K, et al. Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila. PLoS Genet. 2013;9: e1003911. doi: 10.1371/journal.pgen.1003911 24204314

48. Cukier HN, Perez AM, Collins AL, Zhou Z, Zoghbi HY, Botas J. Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet. 2008;4: e1000179. doi: 10.1371/journal.pgen.1000179 18773074

49. Bilen J, Bonini NM. Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet. 2007;3: 1950–64. doi: 10.1371/journal.pgen.0030177 17953484

50. Neufeld TP, Tang AH, Rubin GM. A genetic screen to identify components of the sina signaling pathway in Drosophila eye development. Genetics. 1998;148: 277–286. 9475739

51. Cagan RL, Ready DF. The emergence of order in the Drosophila pupal retina. Dev Biol. 1989;136: 346–362. doi: 10.1016/0012-1606(89)90261-3 2511048

52. Kumar JP. Building an ommatidium one cell at a time. Dev Dyn. 2012;241: 136–149. doi: 10.1002/dvdy.23707 22174084

53. Iyer J, Wang Q, Le T, Pizzo L, Grönke S, Ambegaokar SS, et al. Quantitative assessment of eye phenotypes for functional genetic studies using Drosophila melanogaster. G3 Genes, Genomes, Genet. 2016;6: 1427–1437. doi: 10.1534/g3.116.027060 26994292

54. Grice SJ, Liu J-L, Webber C. Synergistic Interactions between Drosophila Orthologues of Genes Spanned by De Novo Human CNVs Support Multiple-Hit Models of Autism. PLOS Genet. 2015;11: e1004998. doi: 10.1371/journal.pgen.1004998 25816101

55. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010;38: W214–20. doi: 10.1093/nar/gkq537 20576703

56. Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, et al. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015;47: 569–576. doi: 10.1038/ng.3259 25915600

57. Krishnan A, Zhang R, Yao V, Theesfeld CL, Wong AK, Tadych A, et al. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat Neurosci. 2016;19: 1454–1462. doi: 10.1038/nn.4353 27479844

58. Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005;8: 1586–1594. doi: 10.1038/nn1562 16234811

59. Yamaguchi Y, Miura M. Programmed Cell Death in Neurodevelopment. Dev Cell. 2015;32: 478–490. doi: 10.1016/j.devcel.2015.01.019 25710534

60. Ernst C. Proliferation and Differentiation Deficits are a Major Convergence Point for Neurodevelopmental Disorders. Trends Neurosci. 2016;39: 290–299. doi: 10.1016/j.tins.2016.03.001 27032601

61. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466: 368–372. doi: 10.1038/nature09146 20531469

62. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res. 2006;81: 47–63. doi: 10.1016/j.schres.2005.08.014 16226876

63. Steller H. Regulation of apoptosis in Drosophila. Cell Death Differ. 2008;15: 1132–1138. doi: 10.1038/cdd.2008.50 18437164

64. Coe BP, Girirajan S, Eichler EE. A genetic model for neurodevelopmental disease. Curr Opin Neurobiol. 2012;22: 829–836. doi: 10.1016/j.conb.2012.04.007 22560351

65. Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, et al. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46: 249–253. doi: 10.1136/jmg.2008.062380 19028728

66. Coba MP, Ramaker MJ, Ho E V, Thompson SL, Komiyama NH, Grant SGN, et al. Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability. Sci Rep. 2018;8: 2281. doi: 10.1038/s41598-018-20610-y 29396406

67. Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. Cell Rep. 2015;11: 1400–1413. doi: 10.1016/j.celrep.2015.04.064 26027926

68. Park E, Na M, Choi J, Kim S, Lee J-R, Yoon J, et al. The Shank Family of Postsynaptic Density Proteins Interacts with and Promotes Synaptic Accumulation of the βPIX Guanine Nucleotide Exchange Factor for Rac1 and Cdc42. J Biol Chem. 2003;278: 19220–19229. doi: 10.1074/jbc.M301052200 12626503

69. Saiga T, Fukuda T, Matsumoto M, Tada H, Okano HJ, Okano H, et al. Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development. Mol Cell Biol. 2009;29: 3529–3543. doi: 10.1128/MCB.00364-09 19398581

70. Marlin JW, Chang YWE, Ober M, Handy A, Xu W, Jakobi R. Functional PAK-2 knockout and replacement with a caspase cleavage-deficient mutant in mice reveals differential requirements of full-length PAK-2 and caspase-activated PAK-2p34. Mamm Genome. 2011;22: 306–317. doi: 10.1007/s00335-011-9326-6 21499899

71. Wang L, Magdaleno S, Tabas I, Jackowski S. Early Embryonic Lethality in Mice with Targeted Deletion of the CTP:Phosphocholine Cytidylyltransferase Gene (Pcyt1a). Mol Cell Biol. 2005;25: 3357–3363. doi: 10.1128/MCB.25.8.3357-3363.2005 15798219

72. Wang Y, Zeng C, Li J, Zhou Z, Ju X, Xia S, et al. PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior. Cell Rep. 2018;24: 2029–2041. doi: 10.1016/j.celrep.2018.07.061 30134165

73. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21: 396–399. doi: 10.1038/7727 10192390

74. Eicher JD, Landowski C, Stackhouse B, Sloan A, Chen W, Jensen N, et al. GRASP v2.0: An update on the Genome-Wide Repository of Associations between SNPs and Phenotypes. Nucleic Acids Res. 2015;43: D799–D804. doi: 10.1093/nar/gku1202 25428361

75. Turner TN, Yi Q, Krumm N, Huddleston J, Hoekzema K, Stessman HAF, et al. denovo-db: A compendium of human de novo variants. Nucleic Acids Res. 2017;45: D804–D811. doi: 10.1093/nar/gkw865 27907889

76. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506: 185–190. doi: 10.1038/nature12975 24463508

77. Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, et al. SFARI Gene 2.0: A community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism. 2013;4: 36. doi: 10.1186/2040-2392-4-36 24090431

78. Pabis M, Neufeld N, Shav-Tal Y, Neugebauer KM. Binding properties and dynamic localization of an alternative isoform of the cap-binding complex subunit CBP20. Nucleus. 2010;1: 412–21. doi: 10.4161/nucl.1.5.12839 21326824

79. Maquat LE. Nonsense-mediated mRNA decay: Splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol. 2004;5: 89–99. doi: 10.1038/nrm1310 15040442

80. Gonatopoulos-Pournatzis T, Cowling VH. Cap-binding complex (CBC). Biochem J. 2014;457: 231–242. doi: 10.1042/BJ20131214 24354960

81. Xu D, Woodfield SE, Lee T V, Fan Y, Antonio C, Bergmann A. Genetic control of programmed cell death (apoptosis) in Drosophila. Fly (Austin). 2009;3: 78–90. doi: 10.4161/fly.3.1.7800 19182545

82. Kornbluth S, White K. Apoptosis in Drosophila: Neither fish nor fowl (nor man, nor worm). J Cell Sci. 2005;118: 1779–1787. doi: 10.1242/jcs.02377 15860727

83. Tittel JN, Steller H. A comparison of programmed cell death between species. Genome Biol. 2000;1: REVIEWS0003. doi: 10.1186/gb-2000-1-3-reviews0003 11178240

84. Bilder D, Li M, Perrimon N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science. 2000;289: 113–116. doi: 10.1126/science.289.5476.113 10884224

85. Humbert P, Russell S, Richardson H. Dlg, scribble and Lgl in cell polarity, cell proliferation and cancer. BioEssays. 2003;25: 542–553. doi: 10.1002/bies.10286 12766944

86. Shin EY, Shin KS, Lee CS, Woo KN, Quan SH, Soung NK, et al. Phosphorylation of p85 βPIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth. J Biol Chem. 2002;277: 44417–44430. doi: 10.1074/jbc.M203754200 12226077

87. Luo S, Rubinsztein DC. Huntingtin promotes cell survival by preventing Pak2 cleavage. J Cell Sci. 2009;122: 875–885. doi: 10.1242/jcs.050013 19240112

88. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA—J Am Med Assoc. 2011;306: 2001–2010. doi: 10.1001/jama.2011.1638 22068992

89. Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, et al. Volume, neuron density and total neuron number in five subcortical regions in schizophrenia. Brain. 2007;130: 678–692. doi: 10.1093/brain/awl386 17303593

90. Dong D, Zielke HR, Yeh D, Yang P. Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res. 2018;11: 1076–1090. doi: 10.1002/aur.1966 29761862

91. Batalla A, Bargalló N, Gassó P, Molina O, Pareto D, Mas S, et al. Apoptotic markers in cultured fibroblasts correlate with brain metabolites and regional brain volume in antipsychotic-naive first-episode schizophrenia and healthy controls. Transl Psychiatry. 2015;5: e626. doi: 10.1038/tp.2015.122 26305477

92. Gassó P, Mas S, Molina O, Lafuente A, Bernardo M, Parellada E. Increased susceptibility to apoptosis in cultured fibroblasts from antipsychotic-naïve first-episode schizophrenia patients. J Psychiatr Res. 2014;48: 94–101. doi: 10.1016/j.jpsychires.2013.09.017 24128664

93. Thormann A, Halachev M, McLaren W, Moore DJ, Svinti V, Campbell A, et al. Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019;10: 2373. doi: 10.1038/s41467-019-10016-3 31147538

94. Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants. N Engl J Med. 2012;367: 1321–1331. doi: 10.1056/NEJMoa1200395 22970919

95. Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T, Pramparo T, et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410: 97–101. doi: 10.1038/35065105 11242049

96. Poulton CJ, Schot R, Kia SK, Jones M, Verheijen FW, Venselaar H, et al. Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Genet. 2011;89: 265–276. doi: 10.1016/j.ajhg.2011.07.006 21835305

97. Silver DL, Watkins-Chow DE, Schreck KC, Pierfelice TJ, Larson DM, Burnetti AJ, et al. The exon junction complex component Magoh controls brain size by regulating neural stem cell division. Nat Neurosci. 2010;13: 551–558. doi: 10.1038/nn.2527 20364144

98. Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA, Ilyas AM, et al. Molecular genetics of human primary microcephaly: an overview. BMC Med Genomics. 2015;8: S4. doi: 10.1186/1755-8794-8-S1-S4 25951892

99. Frappart P-O, Tong W-M, Demuth I, Radovanovic I, Herceg Z, Aguzzi A, et al. An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med. 2005;11: 538–544. doi: 10.1038/nm1228 15821748

100. Hu Y, Flockhart I, Vinayagam A, Bergwitz C, Berger B, Perrimon N, et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics. 2011;12: 357. doi: 10.1186/1471-2105-12-357 21880147

101. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, et al. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2017;45: D183–D189. doi: 10.1093/nar/gkw1138 27899595

102. Dietzl G, Chen D, Schnorrer F, Su K-C, Barinova Y, Fellner M, et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature. 2007;448: 151–6. doi: 10.1038/nature05954 17625558

103. Green EW, Fedele G, Giorgini F, Kyriacou CP. A Drosophila RNAi collection is subject to dominant phenotypic effects. Nat Methods. 2014;11: 222–223. doi: 10.1038/nmeth.2856 24577271

104. Chintapalli VR, Wang J, Dow JAT. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet. 2007;39: 715–720. doi: 10.1038/ng2049 17534367

105. Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, Yang L, et al. The developmental transcriptome of Drosophila melanogaster. Nature. 2011;471: 473–479. doi: 10.1038/nature09715 21179090

106. Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012;13: 134. doi: 10.1186/1471-2105-13-134 22708584

107. Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods. 2001;25: 402–408. doi: 10.1006/meth.2001.1262 11846609

108. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9: 671–675. doi: 10.1038/nmeth.2089 22930834

109. Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

110. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14: R36. doi: 10.1186/gb-2013-14-4-r36 23618408

111. Anders S, Pyl PT, Huber W. HTSeq-A Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31: 166–169. doi: 10.1093/bioinformatics/btu638 25260700

112. Robinson MD, McCarthy DJ, Smyth GK. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009;26: 139–140. doi: 10.1093/bioinformatics/btp616 19910308

113. Dougherty JD, Schmidt EF, Nakajima M, Heintz N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38: 4218–4230. doi: 10.1093/nar/gkq130 20308160

114. Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508: 199–206. doi: 10.1038/nature13185 24695229

115. Sive HL, Grainger RM, Harland RM. Microinjection of Xenopus Oocytes. Cold Spring Harb Protoc. 2010;2010: pdb.prot5536. doi: 10.1101/pdb.prot5536 21123423

116. Lowery LA, Faris AER, Stout A, Van Vactor D. Neural Explant Cultures from Xenopus laevis. J Vis Exp. 2012; e4232. doi: 10.3791/4232 23295240

117. Nieuwkoop PD, Faber J. Normal table of Xenopus laevis (Daudin) : a systematical and chronological survey of the development from the fertilized egg till the end of metamorphosis. New York : Garland Pub; 1994.

118. Hagberg AA, Schult DA, Swart PJ. Exploring network structure, dynamics, and function using NetworkX. 7th Python in Science Conference (SciPy 2008). 2008. pp. 11–15.

119. Carbon S, Ireland A, Mungall CJ, Shu S, Marshall B, Lewis S, et al. AmiGO: Online access to ontology and annotation data. Bioinformatics. 2009;25: 288–289. doi: 10.1093/bioinformatics/btn615 19033274

120. Karimi K, Fortriede JD, Lotay VS, Burns KA, Wang DZ, Fisher ME, et al. Xenbase: A genomic, epigenomic and transcriptomic model organism database. Nucleic Acids Res. 2018;46: D861–D868. doi: 10.1093/nar/gkx936 29059324

121. Greenwood S, Struhl G. Progression of the morphogenetic furrow in the Drosophila eye: The roles of Hedgehog, Decapentaplegic and the Raf pathway. Development. 1999;126: 5795–5808. 10572054

122. Thurmond J, Goodman JL, Strelets VB, Attrill H, Gramates LS, Marygold SJ, et al. FlyBase 2.0: The next generation. Nucleic Acids Res. 2019;47: D759–D765. doi: 10.1093/nar/gky1003 30364959

123. Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, Anagnostopoulos A, et al. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 2019;47: D801–D806. doi: 10.1093/nar/gky1056 30407599

124. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes. PLoS Genet. 2013;9: e1003709. doi: 10.1371/journal.pgen.1003709 23990802

125. Lek M, Karczewski KJ, Minikel E V., Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536: 285–291. doi: 10.1038/nature19057 27535533

126. O’Leary NA, Wright MW, Brister JR, Ciufo S, Haddad D, McVeigh R, et al. Reference sequence (RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 2016;44: D733–D745. doi: 10.1093/nar/gkv1189 26553804

127. Consortium UniProt. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2018;46: 2699–2699. doi: 10.1093/nar/gky092 29425356

128. The Gene Ontology Consortium. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47: D330–D338. doi: 10.1093/nar/gky1055 30395331

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Třikrát z interní medicíny
nový kurz
Autoři: MUDr. Jana Kubátová

Pokročilá Parkinsonova nemoc − úskalí a možnosti léčby
Autoři: doc. MUDr. Marek Baláž, Ph.D.

Léčba diabetes mellitus 2. typu pomocí GLP- 1 RA

Depresivní porucha a zánětlivé procesy
Autoři: MUDr. Juraj Tkáč

Methotrexát a jeho formy podávání v revmatologii
Autoři: MUDr. Liliana Šedová

Všechny kurzy
Zapomenuté heslo

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


Nemáte účet?  Registrujte se