Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

  • Jose L. Salazar
  • Shinya YamamotoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)


Notch signaling research dates back to more than one hundred years, beginning with the identification of the Notch mutant in the fruit fly Drosophila melanogaster. Since then, research on Notch and related genes in flies has laid the foundation of what we now know as the Notch signaling pathway. In the 1990s, basic biological and biochemical studies of Notch signaling components in mammalian systems, as well as identification of rare mutations in Notch signaling pathway genes in human patients with rare Mendelian diseases or cancer, increased the significance of this pathway in human biology and medicine. In the 21st century, Drosophila and other genetic model organisms continue to play a leading role in understanding basic Notch biology. Furthermore, these model organisms can be used in a translational manner to study underlying mechanisms of Notch-related human diseases and to investigate the function of novel disease associated genes and variants. In this chapter, we first briefly review the major contributions of Drosophila to Notch signaling research, discussing the similarities and differences between the fly and human pathways. Next, we introduce several biological contexts in Drosophila in which Notch signaling has been extensively characterized. Finally, we discuss a number of genetic diseases caused by mutations in genes in the Notch signaling pathway in humans and we expand on how Drosophila can be used to study rare genetic variants associated with these and novel disorders. By combining modern genomics and state-of-the art technologies, Drosophila research is continuing to reveal exciting biology that sheds light onto mechanisms of disease.


Notch signaling Drosophila Mendelian diseases Functional genomics Translational research 



Alzheimer’s disease


A Disintegrin and Metalloprotease 10


Amino-terminal Enhancer of Split






Adams-Oliver Syndrome


Adaptor Protein-3


Anterior pharynx defective


APOlipoprotein E


Amyloid Precursor Protein


atypical Protein Kinase C


Rho GTPase-activating protein 31


Actin-related protein 2/3


Achaete-Scute Complex


Bacterial Artificial Chromosome


big brain


Bloomington Drosophila Stock Center


basic Helix-Loop-Helix

C. elegans

Caenorhabditis elegans


Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy


C-Adenosine Mono Phosphate Responsive Element (cAMP-RE)-Binding protein (CREB)-Binding Protein


Cyclin-Dependent Kinase 8


cAMP response element binding protein


complementary DeoxyriboNucleic Acid


Cohorts for Heart and Aging Research in Genomic Epidemiology


Clustered Regularly Interspaced Short Palindromic Repeats


C-terminal Binding Protein


DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources


Dominant Female Sterile


Drosophila Genomics and Genetic Resources


Drosophila Genomics Resource Center


Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool






Dedicator Of Cytokinesis 6


Developmental Studies Hybridoma Bank




Enhancer of split-Complex


Epidermal Growth Factor


EH (Eps15 Homology) domain Binding Protein-1


embryonic lethal abnormal vision


Ethyl MethaneSulfonate


EGF-domain O-GlcNAc transferase


E1A binding protein P300


Endoplasmic Reticulum


Endosomal Sorting Complex Required for Transport


Familial Alzheimer’s Disease


F-BoX and WD repeat domain containing 7


Four and a Half LIM domains 1






Flippase Recognition Target


GTPase-Activating Protein


Guanine nucleotide Exchange Factor


Genotype to Mendelian Phenotype Browser


Growth Factor Independent 1 transcriptional repressor




abnormal germ line proliferation-1


Granular Osmophilic Material




Genome-Wide Association Studies




hours After Puparium Formation


Human genome organization gene nomenclature committee Comparison of Orthology Predictions search


Homology Directed Repair


Hairy and Enhancer of Split


Hairy/Enhancer-of-split related with YRPW motif


HOmotypic fusion and Protein Sorting


Infantile MyoFibromatosis






lethal (2) giant discs 1


Lunatic FriNGe


Lin11, Isl-1 and Mec-3


cell lineage defective-12


Lateral MeNingocele Syndrome


Lin-12/Notch Repeat


Late-Onset Alzheimer’s Disease


Left Ventricular NonCompaction






Model organism Aggregated Resources for Rare Variant ExpLoration


Mesoderm posterior bHLH transcription factor 2


Manic FriNGe


Mouse Genome Informatics




Minos-Mediated Integration Cassette


messenger RiboNucleic Acid








Notch EXtracellular Truncation


Notch IntraCellular Domain


Negative Regulatory Region




Online Mendelian Inheritance in Man


Platelet Derived Growth Factor Receptor Beta


presenilin enhancer


proline (P), glutamic acid (E), serine (S) and threonine (T)-rich


Protein O-fucosyltransferase 1


Protein O-glucosyltransferase 1


Post-Translational Modification




Recombination signal Binding Protein for immunoglobulin kappa J region


Radical FriNGe


RIPPLY transcriptional repressor 2


Recombinase Mediated Cassette Exchange


RNA interference


Splice Acceptor


SpondyloCostal DysOstosis


Secretory 15




Saccharomyces Genome Database


SMRT/HDAC1 Associated Repressor Protein




Sensory Organ Precursor




SPlit ENds family transcriptional repressor




Suppressor of deltex


Suppressor of Hairless


T-BoX 6




Transducin Like Enhancer protein


TM2 Domain containing 3


Upstream Activation Sequence


Vacuolar-Adenosine TriPhos-phatase


Vienna Drosophila Resource Center


Variant of Unknown Significance


Wiskott-Aldrich Syndrome protein




ZebraFish Information Network



We apologize to our colleagues whose works we were not able to include. We thank Drs. Andrew K. Groves, Hamed Jafar-Nejad, Hillary K. Graves and Michael F. Wangler for constructive comments and helpful suggestions. S.Y. is supported by the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital (NRI Fellowship), the Naman Family Fund for Basic Research and the Caroline Wiess Law Fund for Research in Molecular Medicine (BCM Junior Faculty Seed Funding Program), Alzheimer’s Association (NIRH-15-364099), Simons Foundation Autism Research Initiative (Award#368479), and the National Institutes of Health (NIH, U54 NS093793). J.L.S. received support from the NIH (GMR2556929).


  1. Ables JL, Breunig JJ, Eisch AJ, Rakic P (2011) Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci 12(5):269–283CrossRefPubMedPubMedCentralGoogle Scholar
  2. Acar M, Jafar-Nejad H, Giagtzoglou N, Yallampalli S, David G, He Y, Delidakis C, Bellen HJ (2006) Senseless physically interacts with proneural proteins and functions as a transcriptional co-activator. Development 133(10):1979–1989CrossRefPubMedGoogle Scholar
  3. Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ (2008) Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132(2):247–258CrossRefPubMedPubMedCentralGoogle Scholar
  4. Adam JC, Montell DJ (2004) A role for extra macrochaetae downstream of Notch in follicle cell differentiation. Development 131(23):5971–5980CrossRefPubMedGoogle Scholar
  5. Adams FH, Oliver CP (1945) Hereditary deformities in man due to arrested development. J Hered 36:3–7CrossRefGoogle Scholar
  6. Akazawa C, Sasai Y, Nakanishi S, Kageyama R (1992) Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. J Biol Chem 267(30):21879–21885PubMedGoogle Scholar
  7. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP (1987) Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110(2):195–200CrossRefPubMedGoogle Scholar
  8. Alexandre C, Baena-Lopez A, Vincent JP (2014) Patterning and growth control by membrane-tethered wingless. Nature 505(7482):180–185CrossRefPubMedGoogle Scholar
  9. Altenhoff AM, Dessimoz C (2012) Inferring orthology and paralogy. Methods Mol Biol 855:259–279CrossRefPubMedGoogle Scholar
  10. Alzforum (2017) Scholar
  11. Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodriguez-Falcon M, Villen J, Gygi S, Lopera F, Kalimo H, Moskowitz MA, Ayata C, Louvi A, Artavanis-Tsakonas S (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108(21):E128–E135CrossRefPubMedPubMedCentralGoogle Scholar
  12. Artavanis-Tsakonas S, Muskavitch MA (2010) Notch: the past, the present, and the future. Curr Top Dev Biol 92:1–29CrossRefPubMedGoogle Scholar
  13. Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268(5208):225–232CrossRefPubMedGoogle Scholar
  14. Ayata C (2010) CADASIL: experimental insights from animal models. Stroke 41(10 Suppl):S129–S134CrossRefPubMedPubMedCentralGoogle Scholar
  15. Babaoglan AB, Housden BE, Furriols M, Bray SJ (2013) Deadpan contributes to the robustness of the notch response. PLoS One 8(9):e75632CrossRefPubMedPubMedCentralGoogle Scholar
  16. Bachmann A, Knust E (1998a) Dissection of cis-regulatory elements of the Drosophila gene Serrate. Dev Genes Evol 208(6):346–351CrossRefPubMedGoogle Scholar
  17. Bachmann A, Knust E (1998b) Positive and negative control of Serrate expression during early development of the Drosophila wing. Mech Dev 76(1–2):67–78CrossRefPubMedGoogle Scholar
  18. Bailey AM, Posakony JW (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9(21):2609–2622CrossRefPubMedGoogle Scholar
  19. Bang AG, Posakony JW (1992) The Drosophila gene Hairless encodes a novel basic protein that controls alternative cell fates in adult sensory organ development. Genes Dev 6(9):1752–1769CrossRefPubMedGoogle Scholar
  20. Barad O, Hornstein E, Barkai N (2011) Robust selection of sensory organ precursors by the Notch-Delta pathway. Curr Opin Cell Biol 23(6):663–667CrossRefPubMedGoogle Scholar
  21. Barolo S, Walker RG, Polyanovsky AD, Freschi G, Keil T, Posakony JW (2000) A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology. Cell 103(6):957–969CrossRefPubMedGoogle Scholar
  22. Barolo S, Stone T, Bang AG, Posakony JW (2002) Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes Dev 16(15):1964–1976CrossRefPubMedPubMedCentralGoogle Scholar
  23. Baron M (2012) Endocytic routes to Notch activation. Semin Cell Dev Biol 23(4):437–442CrossRefPubMedGoogle Scholar
  24. Basmanav FB, Oprisoreanu AM, Pasternack SM, Thiele H, Fritz G, Wenzel J, Grosser L, Wehner M, Wolf S, Fagerberg C, Bygum A, Altmuller J, Rutten A, Parmentier L, El Shabrawi-Caelen L, Hafner C, Nurnberg P, Kruse R, Schoch S, Hanneken S, Betz RC (2014) Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am J Hum Genet 94(1):135–143CrossRefPubMedPubMedCentralGoogle Scholar
  25. Bellen HJ, Yamamoto S (2015) Morgan's legacy: fruit flies and the functional annotation of conserved genes. Cell 163(1):12–14CrossRefPubMedPubMedCentralGoogle Scholar
  26. Bender LB, Kooh PJ, Muskavitch MA (1993) Complex function and expression of Delta during Drosophila oogenesis. Genetics 133(4):967–978PubMedPubMedCentralGoogle Scholar
  27. Ben-Yaacov S, Le Borgne R, Abramson I, Schweisguth F, Schejter ED (2001) Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling. J Cell Biol 152(1):1–13CrossRefPubMedPubMedCentralGoogle Scholar
  28. Berdnik D, Torok T, Gonzalez-Gaitan M, Knoblich JA (2002) The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. Dev Cell 3(2):221–231CrossRefPubMedGoogle Scholar
  29. Bergmann M, Ebke M, Yuan Y, Bruck W, Mugler M, Schwendemann G (1996) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family. Acta Neuropathol 92(4):341–350CrossRefPubMedGoogle Scholar
  30. Bernard F, Krejci A, Housden B, Adryan B, Bray SJ (2010) Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors. Development 137(16):2633–2642CrossRefPubMedPubMedCentralGoogle Scholar
  31. Berns N, Woichansky I, Friedrichsen S, Kraft N, Riechmann V (2014) A genome-scale in vivo RNAi analysis of epithelial development in Drosophila identifies new proliferation domains outside of the stem cell niche. J Cell Sci 127(Pt 12):2736–2748CrossRefPubMedGoogle Scholar
  32. Bi P, Kuang S (2015) Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab 26(5):248–255CrossRefPubMedPubMedCentralGoogle Scholar
  33. Blair SS (2007) Wing vein patterning in Drosophila and the analysis of intercellular signaling. Annu Rev Cell Dev Biol 23:293–319CrossRefPubMedGoogle Scholar
  34. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S (1997) Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 90(2):281–291CrossRefPubMedPubMedCentralGoogle Scholar
  35. Blochlinger K, Bodmer R, Jack J, Jan LY, Jan YN (1988) Primary structure and expression of a product from cut, a locus involved in specifying sensory organ identity in Drosophila. Nature 333(6174):629–635CrossRefPubMedGoogle Scholar
  36. Bloomington Drosophila Stock Center (2017)
  37. Borggrefe T, Oswald F (2014) Keeping notch target genes off: a CSL corepressor caught in the act. Structure 22(1):3–5CrossRefPubMedGoogle Scholar
  38. Borggrefe T, Oswald F (2016) Setting the stage for notch: the Drosophila Su(H)-Hairless repressor complex. PLoS Biol 14(7):e1002524CrossRefPubMedPubMedCentralGoogle Scholar
  39. Boulianne GL, de la Concha A, Campos-Ortega JA, Jan LY, Jan YN (1991) The Drosophila neurogenic gene neuralized encodes a novel protein and is expressed in precursors of larval and adult neurons. EMBO J 10(10):2975–2983PubMedPubMedCentralCrossRefGoogle Scholar
  40. Bourgouin C, Lundgren SE, Thomas JB (1992) Apterous is a Drosophila LIM domain gene required for the development of a subset of embryonic muscles. Neuron 9(3):549–561CrossRefPubMedGoogle Scholar
  41. Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, Driancourt C, Beau I, Hadchouel M, Meunier-Rotival M (2007) Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: inhibitory effect on Notch signaling. Hum Mol Genet 16(22):2683–2692CrossRefPubMedGoogle Scholar
  42. Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118(2):401–415PubMedGoogle Scholar
  43. Bray S (1998) Notch signalling in Drosophila: three ways to use a pathway. Semin Cell Dev Biol 9(6):591–597CrossRefPubMedGoogle Scholar
  44. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689CrossRefPubMedGoogle Scholar
  45. Bray S, Bernard F (2010) Notch targets and their regulation. Curr Top Dev Biol 92:253–275CrossRefPubMedGoogle Scholar
  46. Bray S, Musisi H, Bienz M (2005) Bre1 is required for Notch signaling and histone modification. Dev Cell 8(2):279–286CrossRefPubMedGoogle Scholar
  47. Bruckner K, Perez L, Clausen H, Cohen S (2000) Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406(6794):411–415CrossRefPubMedPubMedCentralGoogle Scholar
  48. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD (2000) Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 24(4):438–441CrossRefPubMedGoogle Scholar
  49. Busseau I, Diederich RJ, Xu T, Artavanis-Tsakonas S (1994) A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein. Genetics 136(2):585–596PubMedPubMedCentralGoogle Scholar
  50. Campuzano S, Modolell J (1992) Patterning of the Drosophila nervous system: the achaete-scute gene complex. Trends Genet 8(6):202–208CrossRefPubMedGoogle Scholar
  51. de Celis JF, Bray S (1997) Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124(17):3241–3251PubMedGoogle Scholar
  52. de Celis JF, de Celis J, Ligoxygakis P, Preiss A, Delidakis C, Bray S (1996a) Functional relationships between Notch, Su(H) and the bHLH genes of the E(spl) complex: the E(spl) genes mediate only a subset of Notch activities during imaginal development. Development 122(9):2719–2728PubMedGoogle Scholar
  53. de Celis JF, Garcia-Bellido A, Bray SJ (1996b) Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development 122(1):359–369PubMedGoogle Scholar
  54. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG (2009) Cadasil. Lancet Neurol 8(7):643–653CrossRefPubMedGoogle Scholar
  55. Chao HT, Davids M, Burke E, Pappas JG, Rosenfeld JA, McCarty AJ, Davis T, Wolfe L, Toro C, Tifft C, Xia F, Stong N, Johnson TK, Warr CG, Yamamoto S, Adams DR, Markello TC, Gahl WA, Bellen HJ, Wangler MF, Malicdan MC (2017) A syndromic neurodevelopmental disorder caused by de novo variants in EBF3. Am J Hum Genet 100(1):128–137CrossRefPubMedGoogle Scholar
  56. Charng WL, Yamamoto S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Gibbs S, Lu HC, Chen K, Giagtzoglou N, Bellen HJ (2014) Drosophila Tempura, a novel protein prenyltransferase alpha subunit, regulates notch signaling via Rab1 and Rab11. PLoS Biol 12(1):e1001777CrossRefPubMedPubMedCentralGoogle Scholar
  57. Chen BE, Kondo M, Garnier A, Watson FL, Puettmann-Holgado R, Lamar DR, Schmucker D (2006) The molecular diversity of Dscam is functionally required for neuronal wiring specificity in Drosophila. Cell 125(3):607–620CrossRefPubMedGoogle Scholar
  58. Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, Harrell TM, McMillin MJ, Wiszniewski W, Gambin T, Coban Akdemir ZH, Doheny K, Scott AF, Avramopoulos D, Chakravarti A, Hoover-Fong J, Mathews D, Witmer PD, Ling H, Hetrick K, Watkins L, Patterson KE, Reinier F, Blue E, Muzny D, Kircher M, Bilguvar K, Lopez-Giraldez F, Sutton VR, Tabor HK, Leal SM, Gunel M, Mane S, Gibbs RA, Boerwinkle E, Hamosh A, Shendure J, Lupski JR, Lifton RP, Valle D, Nickerson DA, Bamshad MJ (2015) The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet 97(2):199–215CrossRefPubMedPubMedCentralGoogle Scholar
  59. Chou TB, Perrimon N (1992) Use of a yeast site-specific recombinase to produce female germline chimeras in Drosophila. Genetics 131(3):643–653PubMedPubMedCentralGoogle Scholar
  60. ClinVar (2017) Scholar
  61. Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (2017)
  62. Collins KJ, Yuan Z, Kovall RA (2014) Structure and function of the CSL-KyoT2 corepressor complex: a negative regulator of Notch signaling. Structure 22(1):70–81CrossRefPubMedPubMedCentralGoogle Scholar
  63. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261(5123):921–923CrossRefPubMedGoogle Scholar
  64. Cornell M, Evans DA, Mann R, Fostier M, Flasza M, Monthatong M, Artavanis-Tsakonas S, Baron M (1999) The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase. Genetics 152(2):567–576PubMedPubMedCentralGoogle Scholar
  65. Corson F, Couturier L, Rouault H, Mazouni K, Schweisguth F (2017) Self-organized Notch dynamics generate stereotyped sensory organ patterns in Drosophila. Science 356(6337):501CrossRefGoogle Scholar
  66. Couturier L, Schweisguth F (2014) Antibody uptake assay and in vivo imaging to study intracellular trafficking of Notch and Delta in Drosophila. Methods Mol Biol 1187:79–86CrossRefPubMedGoogle Scholar
  67. Cuyvers E, Sleegers K (2016) Genetic variations underlying Alzheimer’s disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15(8):857–868CrossRefPubMedGoogle Scholar
  68. Da Ros VG, Gutierrez-Perez I, Ferres-Marco D, Dominguez M (2013) Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis. PLoS Biol 11(5):e1001554CrossRefPubMedPubMedCentralGoogle Scholar
  69. D’Amato G, Luxan G, de la Pompa JL (2016) Notch signalling in ventricular chamber development and cardiomyopathy. FEBS J 283(23):4223–4237CrossRefPubMedGoogle Scholar
  70. Daniels RW, Rossano AJ, Macleod GT, Ganetzky B (2014) Expression of multiple transgenes from a single construct using viral 2A peptides in Drosophila. PLoS One 9(6):e100637CrossRefPubMedPubMedCentralGoogle Scholar
  71. Database of Genomic Variants (2017)
  72. DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (2017)
  73. David-Morrison G, Xu Z, Rui YN, Charng WL, Jaiswal M, Yamamoto S, Xiong B, Zhang K, Sandoval H, Duraine L, Zuo Z, Zhang S, Bellen HJ (2016) WAC regulates mTOR activity by acting as an adaptor for the TTT and Pontin/Reptin complexes. Dev Cell 36(2):139–151CrossRefPubMedPubMedCentralGoogle Scholar
  74. Dehal P, Boore JL (2005) Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol 3(10):e314CrossRefPubMedPubMedCentralGoogle Scholar
  75. Delidakis C, Artavanis-Tsakonas S (1992) The Enhancer of split [E(spl)] locus of Drosophila encodes seven independent helix-loop-helix proteins. Proc Natl Acad Sci U S A 89(18):8731–8735CrossRefPubMedPubMedCentralGoogle Scholar
  76. Delidakis C, Preiss A, Hartley DA, Artavanis-Tsakonas S (1991) Two genetically and molecularly distinct functions involved in early neurogenesis reside within the Enhancer of split locus of Drosophila melanogaster. Genetics 129(3):803–823PubMedPubMedCentralGoogle Scholar
  77. Delidakis C, Monastirioti M, Magadi SS (2014) E(spl): genetic, developmental, and evolutionary aspects of a group of invertebrate Hes proteins with close ties to Notch signaling. Curr Top Dev Biol 110:217–262CrossRefPubMedGoogle Scholar
  78. Dell’Angelica EC (2009) AP-3-dependent trafficking and disease: the first decade. Curr Opin Cell Biol 21(4):552–559CrossRefPubMedGoogle Scholar
  79. Developmental Studies Hybridoma Bank (2017)
  80. Dexter JS (1914) The analysis of a case of continuous variation in Drosophila by a study of its linkage relations. Am Nat 48:712–758CrossRefGoogle Scholar
  81. Diao F, White BH (2012) A novel approach for directing transgene expression in Drosophila: T2A-Gal4 in-frame fusion. Genetics 190(3):1139–1144CrossRefPubMedPubMedCentralGoogle Scholar
  82. Diao F, Ironfield H, Luan H, Diao F, Shropshire WC, Ewer J, Marr E, Potter CJ, Landgraf M, White BH (2015) Plug-and-play genetic access to drosophila cell types using exchangeable exon cassettes. Cell Rep 10(8):1410–1421CrossRefPubMedPubMedCentralGoogle Scholar
  83. Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T (2000) Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet 8(4):280–285CrossRefPubMedGoogle Scholar
  84. Digilio MC, Luca AD, Lepri F, Guida V, Ferese R, Dentici ML, Angioni A, Marino B, Dallapiccola B (2013) JAG1 mutation in a patient with deletion 22q11.2 syndrome and tetralogy of Fallot. Am J Med Genet A 161A(12):3133–3136CrossRefPubMedGoogle Scholar
  85. Djiane A, Krejci A, Bernard F, Fexova S, Millen K, Bray SJ (2013) Dissecting the mechanisms of Notch induced hyperplasia. EMBO J 32(1):60–71CrossRefPubMedGoogle Scholar
  86. Doherty D, Feger G, Younger-Shepherd S, Jan LY, Jan YN (1996) Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. Genes Dev 10(4):421–434CrossRefPubMedGoogle Scholar
  87. Domanitskaya E, Schupbach T (2012) CoREST acts as a positive regulator of Notch signaling in the follicle cells of Drosophila melanogaster. J Cell Sci 125(Pt 2):399–410CrossRefPubMedPubMedCentralGoogle Scholar
  88. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18(22):2730–2735CrossRefPubMedPubMedCentralGoogle Scholar
  89. Donahue CP, Kosik KS (2004) Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 83(1):59–65CrossRefPubMedGoogle Scholar
  90. Dornier E, Coumailleau F, Ottavi JF, Moretti J, Boucheix C, Mauduit P, Schweisguth F, Rubinstein E (2012) TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals. J Cell Biol 199(3):481–496CrossRefPubMedPubMedCentralGoogle Scholar
  91. Drosophila Genomics and Genetic Resources (2017)
  92. Drosophila Genomics Resource Center (2017)
  93. Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool (2017)
  94. D'Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92:73–129CrossRefPubMedPubMedCentralGoogle Scholar
  95. Emery G, Hutterer A, Berdnik D, Mayer B, Wirtz-Peitz F, Gaitan MG, Knoblich JA (2005) Asymmetric Rab 11 endosomes regulate delta recycling and specify cell fate in the Drosophila nervous system. Cell 122(5):763–773CrossRefPubMedGoogle Scholar
  96. Eun SH, Lea K, Overstreet E, Stevens S, Lee JH, Fischer JA (2007) Identification of genes that interact with Drosophila liquid facets. Genetics 175(3):1163–1174CrossRefPubMedPubMedCentralGoogle Scholar
  97. Exome Aggregation Consortium Browser (2017)
  98. Ezratty EJ, Stokes N, Chai S, Shah AS, Williams SE, Fuchs E (2011) A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145(7):1129–1141CrossRefPubMedPubMedCentralGoogle Scholar
  99. Fehon RG, Johansen K, Rebay I, Artavanis-Tsakonas S (1991) Complex cellular and subcellular regulation of notch expression during embryonic and imaginal development of Drosophila: implications for notch function. J Cell Biol 113(3):657–669CrossRefPubMedGoogle Scholar
  100. Fleming RJ, Scottgale TN, Diederich RJ, Artavanis-Tsakonas S (1990) The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster. Genes Dev 4(12A):2188–2201CrossRefPubMedGoogle Scholar
  101. Fleming RJ, Gu Y, Hukriede NA (1997) Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124(15):2973–2981PubMedGoogle Scholar
  102. Flood DG, Reaume AG, Dorfman KS, Lin YG, Lang DM, Trusko SP, Savage MJ, Annaert WG, De Strooper B, Siman R, Scott RW (2002) FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction. Neurobiol Aging 23(3):335–348CrossRefPubMedGoogle Scholar
  103. FlyBase (2017)
  104. FlyBase-AP3 (2017) Scholar
  105. FlyBase-ESCRT (2017) Scholar
  106. Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647CrossRefPubMedGoogle Scholar
  107. Fortini ME, Artavanis-Tsakonas S (1994) The suppressor of hairless protein participates in notch receptor signaling. Cell 79(2):273–282CrossRefPubMedGoogle Scholar
  108. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3(1):85–97CrossRefPubMedGoogle Scholar
  109. Furman DP, Bukharina TA (2008) How Drosophila melanogaster forms its mechanoreceptors. Curr Genomics 9(5):312–323CrossRefPubMedPubMedCentralGoogle Scholar
  110. Furukawa T, Kawaichi M, Matsunami N, Ryo H, Nishida Y, Honjo T (1991) The Drosophila RBP-J kappa gene encodes the binding protein for the immunoglobulin J kappa recombination signal sequence. J Biol Chem 266(34):23334–23340PubMedGoogle Scholar
  111. Furukawa T, Maruyama S, Kawaichi M, Honjo T (1992) The Drosophila homolog of the immunoglobulin recombination signal-binding protein regulates peripheral nervous system development. Cell 69(7):1191–1197CrossRefPubMedGoogle Scholar
  112. Fuwa TJ, Hori K, Sasamura T, Higgs J, Baron M, Matsuno K (2006) The first deltex null mutant indicates tissue-specific deltex-dependent Notch signaling in Drosophila. Mol Gen Genomics 275(3):251–263CrossRefGoogle Scholar
  113. Gallagher CM, Knoblich JA (2006) The conserved c2 domain protein lethal (2) giant discs regulates protein trafficking in Drosophila. Dev Cell 11(5):641–653CrossRefPubMedGoogle Scholar
  114. Garcia-Bellido A, Santamaria P (1978) Developmental analysis of the achaete-scute system of Drosophila melanogaster. Genetics 88(3):469–486PubMedPubMedCentralGoogle Scholar
  115. Garg V (2006) Molecular genetics of aortic valve disease. Curr Opin Cardiol 21(3):180–184CrossRefPubMedGoogle Scholar
  116. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437(7056):270–274CrossRefPubMedPubMedCentralGoogle Scholar
  117. Geisler F, Strazzabosco M (2015) Emerging roles of Notch signaling in liver disease. Hepatology 61(1):382–392CrossRefPubMedGoogle Scholar
  118. Geno2MP (2017) Genotype to Mendelian phenotype browser.
  119. Gho M, Bellaiche Y, Schweisguth F (1999) Revisiting the Drosophila microchaete lineage: a novel intrinsically asymmetric cell division generates a glial cell. Development 126(16):3573–3584PubMedGoogle Scholar
  120. Giagtzoglou N, Yamamoto S, Zitserman D, Graves HK, Schulze KL, Wang H, Klein H, Roegiers F, Bellen HJ (2012) dEHBP1 controls exocytosis and recycling of Delta during asymmetric divisions. J Cell Biol 196(1):65–83CrossRefPubMedPubMedCentralGoogle Scholar
  121. Giagtzoglou N, Li T, Yamamoto S, Bellen HJ (2013) Drosophila EHBP1 regulates Scabrous secretion during Notch-mediated lateral inhibition. J Cell Sci 126(Pt 16):3686–3696CrossRefPubMedPubMedCentralGoogle Scholar
  122. Gianni D, Li A, Tesco G, McKay KM, Moore J, Raygor K, Rota M, Gwathmey JK, Dec GW, Aretz T, Leri A, Semigran MJ, Anversa P, Macgillivray TE, Tanzi RE, del Monte F (2010) Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy. Circulation 121(10):1216–1226CrossRefPubMedPubMedCentralGoogle Scholar
  123. Gianni D, Li A, Tesco G, McKay KM, Moore J, Raygor K, Rota M, Gwathmey JK, Dec GW, Aretz T, Leri A, Semigran MJ, Anversa P, Macgillivray TE, Tanzi RE, del Monte F (2011) Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy. Circulation 121(10):1216–1226CrossRefGoogle Scholar
  124. Gigliani F, Longo F, Gaddini L, Battaglia PA (1996) Interactions among the bHLH domains of the proteins encoded by the Enhancer of split and achaete-scute gene complexes of Drosophila. Mol Gen Genet 251(6):628–634PubMedGoogle Scholar
  125. Gnerer JP, Venken KJ, Dierick HA (2015) Gene-specific cell labeling using MiMIC transposons. Nucleic Acids Res 43(8):e56CrossRefPubMedPubMedCentralGoogle Scholar
  126. Go MJ, Artavanis-Tsakonas S (1998) A genetic screen for novel components of the notch signaling pathway during Drosophila bristle development. Genetics 150(1):211–220PubMedPubMedCentralGoogle Scholar
  127. Gomez-Lamarca MJ, Snowdon LA, Seib E, Klein T, Bray SJ (2015) Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling. J Cell Biol 210(2):303–318CrossRefPubMedPubMedCentralGoogle Scholar
  128. Gonzaga-Jauregui C, Lupski JR, Gibbs RA (2012) Human genome sequencing in health and disease. Annu Rev Med 63:35–61CrossRefPubMedPubMedCentralGoogle Scholar
  129. Goode S, Melnick M, Chou TB, Perrimon N (1996) The neurogenic genes egghead and brainiac define a novel signaling pathway essential for epithelial morphogenesis during Drosophila oogenesis. Development 122(12):3863–3879PubMedGoogle Scholar
  130. Goodfellow H, Krejci A, Moshkin Y, Verrijzer CP, Karch F, Bray SJ (2007) Gene-specific targeting of the histone chaperone asf1 to mediate silencing. Dev Cell 13(4):593–600CrossRefPubMedGoogle Scholar
  131. Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC (2007) Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14(4):295–300CrossRefPubMedGoogle Scholar
  132. Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC (2009a) Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One 4(8):e6613CrossRefPubMedPubMedCentralGoogle Scholar
  133. Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR, Aster JC, Blacklow SC (2009b) Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood 113(18):4381–4390CrossRefPubMedPubMedCentralGoogle Scholar
  134. Goto S, Taniguchi M, Muraoka M, Toyoda H, Sado Y, Kawakita M, Hayashi S (2001) UDP-sugar transporter implicated in glycosylation and processing of Notch. Nat Cell Biol 3(9):816–822CrossRefPubMedGoogle Scholar
  135. Gratz SJ, Rubinstein CD, Harrison MM, Wildonger J, O’Connor-Giles KM (2015) CRISPR-Cas9 Genome editing in Drosophila. Curr Protoc Mol Biol 111:31 32 31–20Google Scholar
  136. Green RC, Goddard KA, Jarvik GP, Amendola LM, Appelbaum PS, Berg JS, Bernhardt BA, Biesecker LG, Biswas S, Blout CL, Bowling KM, Brothers KB, Burke W, Caga-Anan CF, Chinnaiyan AM, Chung WK, Clayton EW, Cooper GM, East K, Evans JP, Fullerton SM, Garraway LA, Garrett JR, Gray SW, Henderson GE, Hindorff LA, Holm IA, Lewis MH, Hutter CM, Janne PA, Joffe S, Kaufman D, Knoppers BM, Koenig BA, Krantz ID, Manolio TA, McCullough L, McEwen J, McGuire A, Muzny D, Myers RM, Nickerson DA, Ou J, Parsons DW, Petersen GM, Plon SE, Rehm HL, Roberts JS, Robinson D, Salama JS, Scollon S, Sharp RR, Shirts B, Spinner NB, Tabor HK, Tarczy-Hornoch P, Veenstra DL, Wagle N, Weck K, Wilfond BS, Wilhelmsen K, Wolf SM, Wynn J, Yu JH (2016) Clinical sequencing exploratory research consortium: accelerating evidence-based practice of genomic medicine. Am J Hum Genet 98(6):1051–1066CrossRefPubMedPubMedCentralGoogle Scholar
  137. Gridley T (1997) Notch signaling in vertebrate development and disease. Mol Cell Neurosci 9(2):103–108CrossRefPubMedPubMedCentralGoogle Scholar
  138. Gridley T (2003) Notch signaling and inherited disease syndromes. Hum Mol Genet 12(1):R9–R13CrossRefPubMedPubMedCentralGoogle Scholar
  139. Gridley T (2010) Notch signaling in the vasculature. Curr Top Dev Biol 92:277–309CrossRefPubMedPubMedCentralGoogle Scholar
  140. Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K (2015) Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am J Med Genet A 167A(2):271–281CrossRefPubMedPubMedCentralGoogle Scholar
  141. Guida V, Chiappe F, Ferese R, Usala G, Maestrale G, Iannascoli C, Bellacchio E, Mingarelli R, Digilio MC, Marino B, Uda M, De Luca A, Dallapiccola B (2011) Novel and recurrent JAG1 mutations in patients with tetralogy of Fallot. Clin Genet 80(6):591–594CrossRefPubMedGoogle Scholar
  142. Guo M, Jan LY, Jan YN (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17(1):27–41CrossRefPubMedPubMedCentralGoogle Scholar
  143. Guo Y, Livne-Bar I, Zhou L, Boulianne GL (1999a) Drosophila presenilin is required for neuronal differentiation and affects notch subcellular localization and signaling. J Neurosci 19(19):8435–8442CrossRefPubMedPubMedCentralGoogle Scholar
  144. Guo Q, Fu W, Sopher BL, Miller MW, Ware CB, Martin GM, Mattson MP (1999b) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5(1):101–106CrossRefPubMedGoogle Scholar
  145. Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O, McKillip E, Shah S, Stapleton M, Wan KH, Yu C, Parsa B, Carlson JW, Chen X, Kapadia B, Vijayraghavan K, Gygi SP, Celniker SE, Obar RA, Artavanis-Tsakonas S (2011) A protein complex network of Drosophila melanogaster. Cell 147(3):690–703CrossRefPubMedPubMedCentralGoogle Scholar
  146. Guruharsha KG, Kankel MW, Artavanis-Tsakonas S (2012) The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13(9):654–666CrossRefPubMedPubMedCentralGoogle Scholar
  147. Guruharsha KG, Hori K, Obar RA, Artavanis-Tsakonas S (2014) Proteomic analysis of the Notch interactome. Methods Mol Biol 1187:181–192CrossRefPubMedGoogle Scholar
  148. Haberman AS, Akbar MA, Ray S, Kramer H (2010) Drosophila acinus encodes a novel regulator of endocytic and autophagic trafficking. Development 137(13):2157–2166CrossRefPubMedPubMedCentralGoogle Scholar
  149. Hall LE, Alexander SJ, Chang M, Woodling NS, Yedvobnick B (2004) An EP overexpression screen for genetic modifiers of Notch pathway function in Drosophila melanogaster. Genet Res 83(2):71–82CrossRefPubMedGoogle Scholar
  150. Haritunians T, Chow T, De Lange RP, Nichols JT, Ghavimi D, Dorrani N, St Clair DM, Weinmaster G, Schanen C (2005) Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry 76(9):1242–1248CrossRefPubMedPubMedCentralGoogle Scholar
  151. Hartenstein V, Posakony JW (1989) Development of adult sensilla on the wing and notum of Drosophila melanogaster. Development 107(2):389–405PubMedGoogle Scholar
  152. Hartenstein V, Posakony JW (1990) A dual function of the Notch gene in Drosophila sensillum development. Dev Biol 142(1):13–30CrossRefPubMedGoogle Scholar
  153. Hartley DA, Xu TA, Artavanis-Tsakonas S (1987) The embryonic expression of the Notch locus of Drosophila melanogaster and the implications of point mutations in the extracellular EGF-like domain of the predicted protein. EMBO J 6(11):3407–3417PubMedPubMedCentralCrossRefGoogle Scholar
  154. Hartley DA, Preiss A, Artavanis-Tsakonas S (1988) A deduced gene product from the Drosophila neurogenic locus, enhancer of split, shows homology to mammalian G-protein beta subunit. Cell 55(5):785–795CrossRefPubMedGoogle Scholar
  155. Hassed SJ, Wiley GB, Wang S, Lee JY, Li S, Xu W, Zhao ZJ, Mulvihill JJ, Robertson J, Warner J, Gaffney PM (2012) RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am J Hum Genet 91(2):391–395CrossRefPubMedPubMedCentralGoogle Scholar
  156. Hassed S, Li S, Mulvihill J, Aston C, Palmer S (2017) Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype. Am J Med Genet A 173(3):790–800CrossRefPubMedGoogle Scholar
  157. HCOP (Human Genome Organization Gene Nomenclature Committee Comparison of Orthology Predictions Search) (2017) Scholar
  158. Heitzler P (2010) Biodiversity and noncanonical Notch signaling. Curr Top Dev Biol 92:457–481CrossRefPubMedGoogle Scholar
  159. Heitzler P, Bourouis M, Ruel L, Carteret C, Simpson P (1996) Genes of the Enhancer of split and achaete-scute complexes are required for a regulatory loop between Notch and Delta during lateral signalling in Drosophila. Development 122(1):161–171PubMedGoogle Scholar
  160. Herz HM, Woodfield SE, Chen Z, Bolduc C, Bergmann A (2009) Common and distinct genetic properties of ESCRT-II components in Drosophila. PLoS One 4(1):e4165CrossRefPubMedPubMedCentralGoogle Scholar
  161. Heuss SF, Ndiaye-Lobry D, Six EM, Israel A, Logeat F (2008) The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proc Natl Acad Sci U S A 105(32):11212–11217CrossRefPubMedPubMedCentralGoogle Scholar
  162. Hing HK, Bangalore L, Sun X, Artavanis-Tsakonas S (1999) Mutations in the heatshock cognate 70 protein (hsc4) modulate Notch signaling. Eur J Cell Biol 78(10):690–697CrossRefPubMedGoogle Scholar
  163. Hori K, Sen A, Kirchhausen T, Artavanis-Tsakonas S (2011) Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol 195(6):1005–1015CrossRefPubMedPubMedCentralGoogle Scholar
  164. Housden BE, Fu AQ, Krejci A, Bernard F, Fischer B, Tavare S, Russell S, Bray SJ (2013) Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes. PLoS Genet 9(1):e1003162CrossRefPubMedPubMedCentralGoogle Scholar
  165. Housden BE, Li J, Bray SJ (2014) Visualizing Notch signaling in vivo in Drosophila tissues. Methods Mol Biol 1187:101–113CrossRefPubMedPubMedCentralGoogle Scholar
  166. Huang C, Chan JA, Schuurmans C (2014) Proneural bHLH genes in development and disease. Curr Top Dev Biol 110:75–127CrossRefPubMedGoogle Scholar
  167. Hurlbut GD, Kankel MW, Lake RJ, Artavanis-Tsakonas S (2007) Crossing paths with Notch in the hyper-network. Curr Opin Cell Biol 19(2):166–175CrossRefPubMedGoogle Scholar
  168. Hutterer A, Knoblich JA (2005) Numb and alpha-Adaptin regulate Sanpodo endocytosis to specify cell fate in Drosophila external sensory organs. EMBO Rep 6(9):836–842CrossRefPubMedPubMedCentralGoogle Scholar
  169. Ilagan MX, Kopan R (2007) SnapShot: notch signaling pathway. Cell 128(6):1246CrossRefPubMedGoogle Scholar
  170. Irvine KD, Wieschaus E (1994) fringe, a Boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79(4):595–606CrossRefPubMedGoogle Scholar
  171. Ishiko A, Shimizu A, Nagata E, Takahashi K, Tabira T, Suzuki N (2006) Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL. Acta Neuropathol 112(3):333–339CrossRefPubMedGoogle Scholar
  172. Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C (2011) Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43(4):306–308CrossRefPubMedGoogle Scholar
  173. Jack J, DeLotto Y (1992) Effect of wing scalloping mutations on cut expression and sense organ differentiation in the Drosophila wing margin. Genetics 131(2):353–363PubMedPubMedCentralGoogle Scholar
  174. Jafar-Nejad H, Acar M, Nolo R, Lacin H, Pan H, Parkhurst SM, Bellen HJ (2003) Senseless acts as a binary switch during sensory organ precursor selection. Genes Dev 17(23):2966–2978CrossRefPubMedPubMedCentralGoogle Scholar
  175. Jafar-Nejad H, Andrews HK, Acar M, Bayat V, Wirtz-Peitz F, Mehta SQ, Knoblich JA, Bellen HJ (2005) Sec15, a component of the exocyst, promotes notch signaling during the asymmetric division of Drosophila sensory organ precursors. Dev Cell 9(3):351–363CrossRefPubMedGoogle Scholar
  176. Jafar-Nejad H, Leonardi J, Fernandez-Valdivia R (2010) Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology 20(8):931–949CrossRefPubMedPubMedCentralGoogle Scholar
  177. Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D, Yamamoto S, Grove ML, Naj A, Vronskaya M, Salazar JL, DeStefano AL, Brody JA, Smith AV, Amin N, Sims R, Ibrahim-Verbaas CA, Choi SH, Satizabal CL, Lopez OL, Beiser A, Ikram MA, Garcia ME, Hayward C, Varga TV, Ripatti S, Franks PW, Hallmans G, Rolandsson O, Jansson JH, Porteous DJ, Salomaa V, Eiriksdottir G, Rice KM, Bellen HJ, Levy D, Uitterlinden AG, Emilsson V, Rotter JI, Aspelund T, O’Donnell CJ, Fitzpatrick AL, Launer LJ, Hofman A, Wang LS, Williams J, Schellenberg GD, Boerwinkle E, Psaty BM, Seshadri S, Shulman JM, Gudnason V, van Duijn CM (2016) Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer’s Disease. PLoS Genet 12(10):e1006327Google Scholar
  178. Jan YN, Jan LY (2001) Asymmetric cell division in the Drosophila nervous system. Nat Rev Neurosci 2(11):772–779CrossRefPubMedGoogle Scholar
  179. Jana SC, Bettencourt-Dias M, Durand B, Megraw TL (2016) Drosophila melanogaster as a model for basal body research. Cilia 5:22CrossRefPubMedPubMedCentralGoogle Scholar
  180. Jennings B, Preiss A, Delidakis C, Bray S (1994) The Notch signalling pathway is required for Enhancer of split bHLH protein expression during neurogenesis in the Drosophila embryo. Development 120(12):3537–3548PubMedGoogle Scholar
  181. Jia D, Soylemez M, Calvin G, Bornmann R, Bryant J, Hanna C, Huang YC, Deng WM (2015) A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches. Sci Rep 5:12328CrossRefPubMedPubMedCentralGoogle Scholar
  182. Johansen KM, Fehon RG, Artavanis-Tsakonas S (1989) The notch gene product is a glycoprotein expressed on the cell surface of both epidermal and neuronal precursor cells during Drosophila development. J Cell Biol 109(5):2427–2440CrossRefPubMedGoogle Scholar
  183. Johnson EA (2011) HIF takes it up a notch. Sci Signal 4(181):pe33CrossRefPubMedGoogle Scholar
  184. Joutel A (2011) Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature. Bioessays 33(1):73–80CrossRefPubMedGoogle Scholar
  185. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383(6602):707–710CrossRefPubMedPubMedCentralGoogle Scholar
  186. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350(9090):1511–1515CrossRefPubMedGoogle Scholar
  187. Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E (2000) The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 105(5):597–605CrossRefPubMedPubMedCentralGoogle Scholar
  188. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E (2001) Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 358(9298):2049–2051CrossRefPubMedGoogle Scholar
  189. Joutel A, Monet M, Domenga V, Riant F, Tournier-Lasserve E (2004) Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling Pathway. Am J Hum Genet 74(2):338–347CrossRefPubMedPubMedCentralGoogle Scholar
  190. Kageyama R, Niwa Y, Shimojo H, Kobayashi T, Ohtsuka T (2010) Ultradian oscillations in Notch signaling regulate dynamic biological events. Curr Top Dev Biol 92:311–331CrossRefPubMedGoogle Scholar
  191. Kakuda S, Haltiwanger RS (2017) Deciphering the fringe-mediated Notch code: identification of activating and inhibiting sites allowing discrimination between ligands. Dev Cell 40(2):193–201CrossRefPubMedPubMedCentralGoogle Scholar
  192. Karaca E, Yuregir OO, Bozdogan ST, Aslan H, Pehlivan D, Jhangiani SN, Akdemir ZC, Gambin T, Bayram Y, Atik MM, Erdin S, Muzny D, Gibbs RA, Lupski JR (2015) Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am J Med Genet A 167A(11):2795–2799CrossRefPubMedPubMedCentralGoogle Scholar
  193. Kasahara M (2007) The 2R hypothesis: an update. Curr Opin Immunol 19(5):547–552CrossRefPubMedGoogle Scholar
  194. Katsonis P, Koire A, Wilson SJ, Hsu TK, Lua RC, Wilkins AD, Lichtarge O (2014) Single nucleotide variations: biological impact and theoretical interpretation. Protein Sci 23(12):1650–1666CrossRefPubMedPubMedCentralGoogle Scholar
  195. Kidd S, Lieber T (2002) Furin cleavage is not a requirement for Drosophila Notch function. Mech Dev 115(1–2):41–51CrossRefPubMedGoogle Scholar
  196. Kidd S, Kelley MR, Young MW (1986) Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol Cell Biol 6(9):3094–3108CrossRefPubMedPubMedCentralGoogle Scholar
  197. Kidd S, Baylies MK, Gasic GP, Young MW (1989) Structure and distribution of the Notch protein in developing Drosophila. Genes Dev 3(8):1113–1129CrossRefPubMedGoogle Scholar
  198. Kidd S, Struhl G, Lieber T (2015) Notch is required in adult Drosophila sensory neurons for morphological and functional plasticity of the olfactory circuit. PLoS Genet 11(5):e1005244CrossRefPubMedPubMedCentralGoogle Scholar
  199. Kim J, Irvine KD, Carroll SB (1995) Cell recognition, signal induction, and symmetrical gene activation at the dorsal-ventral boundary of the developing Drosophila wing. Cell 82(5):795–802CrossRefPubMedGoogle Scholar
  200. Kitagawa M, Oyama T, Kawashima T, Yedvobnick B, Kumar A, Matsuno K, Harigaya K (2001) A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters. Mol Cell Biol 21(13):4337–4346CrossRefPubMedPubMedCentralGoogle Scholar
  201. Klambt C, Knust E, Tietze K, Campos-Ortega JA (1989) Closely related transcripts encoded by the neurogenic gene complex enhancer of split of Drosophila melanogaster. EMBO J 8(1):203–210PubMedPubMedCentralCrossRefGoogle Scholar
  202. Klein T, Arias AM (1998) Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125(15):2951–2962PubMedGoogle Scholar
  203. Klein T, Couso JP, Martinez Arias A (1998) Wing development and specification of dorsal cell fates in the absence of apterous in Drosophila. Curr Biol 8(7):417–420CrossRefPubMedGoogle Scholar
  204. Knust E, Schrons H, Grawe F, Campos-Ortega JA (1992) Seven genes of the Enhancer of split complex of Drosophila melanogaster encode helix-loop-helix proteins. Genetics 132(2):505–518PubMedPubMedCentralGoogle Scholar
  205. Kobayashi T, Kageyama R (2014) Expression dynamics and functions of Hes factors in development and diseases. Curr Top Dev Biol 110:263–283CrossRefPubMedGoogle Scholar
  206. Koch U, Radtke F (2010) Notch signaling in solid tumors. Curr Top Dev Biol 92:411–455CrossRefPubMedGoogle Scholar
  207. Koch U, Lehal R, Radtke F (2013) Stem cells living with a Notch. Development 140(4):689–704CrossRefPubMedGoogle Scholar
  208. Kokubo H, Lun Y, Johnson RL (1999) Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split. Biochem Biophys Res Commun 260(2):459–465CrossRefPubMedGoogle Scholar
  209. Kola S, Koneti NR, Golla JP, Akka J, Gundimeda SD, Mundluru HP (2011) Mutational analysis of JAG1 gene in non-syndromic tetralogy of Fallot children. Clin Chim Acta 412(23-24):2232–2236CrossRefPubMedGoogle Scholar
  210. Kono M, Sugiura K, Suganuma M, Hayashi M, Takama H, Suzuki T, Matsunaga K, Tomita Y, Akiyama M (2013) Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease. Hum Mol Genet 22(17):3524–3533CrossRefPubMedGoogle Scholar
  211. Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH, Kim CH, Kong YY (2005) Mind bomb-2 is an E3 ligase for Notch ligand. J Biol Chem 280(23):22335–22342CrossRefPubMedGoogle Scholar
  212. Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY, Kim CH, Suh PG, Jan YN, Kong YY (2007) An obligatory role of mind bomb-1 in notch signaling of mammalian development. PLoS One 2(11):e1221CrossRefPubMedPubMedCentralGoogle Scholar
  213. Kooh PJ, Fehon RG, Muskavitch MA (1993) Implications of dynamic patterns of Delta and Notch expression for cellular interactions during Drosophila development. Development 117(2):493–507PubMedGoogle Scholar
  214. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233CrossRefPubMedPubMedCentralGoogle Scholar
  215. Kopczynski CC, Muskavitch MA (1989) Complex spatio-temporal accumulation of alternative transcripts from the neurogenic gene Delta during Drosophila embryogenesis. Development 107(3):623–636PubMedGoogle Scholar
  216. Kopczynski CC, Alton AK, Fechtel K, Kooh PJ, Muskavitch MA (1988) Delta, a Drosophila neurogenic gene, is transcriptionally complex and encodes a protein related to blood coagulation factors and epidermal growth factor of vertebrates. Genes Dev 2(12b):1723–1735CrossRefPubMedGoogle Scholar
  217. Koutelou E, Sato S, Tomomori-Sato C, Florens L, Swanson SK, Washburn MP, Kokkinaki M, Conaway RC, Conaway JW, Moschonas NK (2008) Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1. J Biol Chem 283(7):3846–3853CrossRefPubMedGoogle Scholar
  218. Kovall RA, Blacklow SC (2010) Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol 92:31–71CrossRefPubMedGoogle Scholar
  219. Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, Goldmuntz E, Spinner NB (1999) Jagged1 mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet 84(1):56–60CrossRefPubMedGoogle Scholar
  220. Krejci A, Bernard F, Housden BE, Collins S, Bray SJ (2009) Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci Signal 2(55):ra1CrossRefPubMedGoogle Scholar
  221. Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T, Taniguchi Y, Kurooka H, Hamada Y, Toyokuni S, Honjo T (2003) Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18(2):301–312CrossRefPubMedGoogle Scholar
  222. Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT, Boulter J, Sun YE, Kintner C, Weinmaster G (2005) The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 170(6):983–992CrossRefPubMedPubMedCentralGoogle Scholar
  223. Lai EC, Orgogozo V (2004) A hidden program in Drosophila peripheral neurogenesis revealed: fundamental principles underlying sensory organ diversity. Dev Biol 269(1):1–17CrossRefPubMedGoogle Scholar
  224. Lai EC, Bodner R, Posakony JW (2000) The enhancer of split complex of Drosophila includes four Notch-regulated members of the bearded gene family. Development 127(16):3441–3455PubMedGoogle Scholar
  225. Lai EC, Deblandre GA, Kintner C, Rubin GM (2001) Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev Cell 1(6):783–794CrossRefPubMedGoogle Scholar
  226. Lai EC, Roegiers F, Qin X, Jan YN, Rubin GM (2005) The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta. Development 132(10):2319–2332CrossRefPubMedGoogle Scholar
  227. Lake RJ, Grimm LM, Veraksa A, Banos A, Artavanis-Tsakonas S (2009) In vivo analysis of the Notch receptor S1 cleavage. PLoS One 4(8):e6728CrossRefPubMedPubMedCentralGoogle Scholar
  228. Langevin J, Le Borgne R, Rosenfeld F, Gho M, Schweisguth F, Bellaiche Y (2005) Lethal giant larvae controls the localization of notch-signaling regulators numb, neuralized, and Sanpodo in Drosophila sensory-organ precursor cells. Curr Biol 15(10):955–962CrossRefPubMedGoogle Scholar
  229. Le Borgne R, Schweisguth F (2003) Unequal segregation of Neuralized biases Notch activation during asymmetric cell division. Dev Cell 5(1):139–148CrossRefPubMedGoogle Scholar
  230. Le Borgne R, Remaud S, Hamel S, Schweisguth F (2005) Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila. PLoS Biol 3(4):e96CrossRefPubMedPubMedCentralGoogle Scholar
  231. Le Bras S, Loyer N, Le Borgne R (2011) The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic 12(2):149–161CrossRefPubMedGoogle Scholar
  232. Lecourtois M, Schweisguth F (1995) The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. Genes Dev 9(21):2598–2608CrossRefPubMedGoogle Scholar
  233. Lee TV, Sethi MK, Leonardi J, Rana NA, Buettner FF, Haltiwanger RS, Bakker H, Jafar-Nejad H (2013) Negative regulation of notch signaling by xylose. PLoS Genet 9(6):e1003547CrossRefPubMedPubMedCentralGoogle Scholar
  234. Lehmann R, Dietrich U, Jiménez F, Campos-Ortega JA (1981) Mutations of early neurogenesis in Drosophila. Wilehm Roux Arch Dev Biol (Dev Genes Evo) 190(4):226–229CrossRefGoogle Scholar
  235. Lehmann R, Jimenez F, Dietrich U, Campos-Ortega JA (1983) On the phenotype and development of mutants of early neurogenesis in Drosophila melanogaster. Wilehm Roux Arch Dev Biol (Dev Genes Evo) 192(2):62–74CrossRefGoogle Scholar
  236. Leimeister C, Externbrink A, Klamt B, Gessler M (1999) Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis. Mech Dev 85(1-2):173–177CrossRefPubMedGoogle Scholar
  237. Leonardi J, Fernandez-Valdivia R, Li YD, Simcox AA, Jafar-Nejad H (2011) Multiple O-glucosylation sites on Notch function as a buffer against temperature-dependent loss of signaling. Development 138(16):3569–3578CrossRefPubMedPubMedCentralGoogle Scholar
  238. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16(3):243–251CrossRefPubMedGoogle Scholar
  239. Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE (2006) Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet 79(6):1030–1039CrossRefPubMedPubMedCentralGoogle Scholar
  240. Li M, Cheng R, Liang J, Yan H, Zhang H, Yang L, Li C, Jiao Q, Lu Z, He J, Ji J, Shen Z, Li C, Hao F, Yu H, Yao Z (2013) Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet 92(6):895–903CrossRefPubMedPubMedCentralGoogle Scholar
  241. Li J, Housden BE, Bray SJ (2014) Notch signaling assays in Drosophila cultured cell lines. Methods Mol Biol 1187:131–141CrossRefPubMedGoogle Scholar
  242. Lieber T, Kidd S, Struhl G (2011) DSL-Notch signaling in the Drosophila brain in response to olfactory stimulation. Neuron 69(3):468–481CrossRefPubMedPubMedCentralGoogle Scholar
  243. Lindsley DL, Zimm GG (1992) The Genome of Drosophila melanogaster. Academic Press, San DiegoGoogle Scholar
  244. Liu J, Sato C, Cerletti M, Wagers A (2010) Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr Top Dev Biol 92:367–409CrossRefPubMedGoogle Scholar
  245. Liu J, Fukunaga-Kalabis M, Li L, Herlyn M (2015) Developmental pathways activated in melanocytes and melanoma. Arch Biochem Biophys 563:13–21CrossRefGoogle Scholar
  246. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israel A (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 95(14):8108–8112CrossRefPubMedPubMedCentralGoogle Scholar
  247. Louvi A, Artavanis-Tsakonas S (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23(4):473–480CrossRefPubMedPubMedCentralGoogle Scholar
  248. Lundkvist J, Zhu S, Hansson EM, Schweinhardt P, Miao Q, Beatus P, Dannaeus K, Karlstrom H, Johansson CB, Viitanen M, Rozell B, Spenger C, Mohammed A, Kalimo H, Lendahl U (2005) Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype. Genesis 41(1):13–22CrossRefPubMedPubMedCentralGoogle Scholar
  249. Luxan G, Casanova JC, Martinez-Poveda B, Prados B, D’Amato G, MacGrogan D, Gonzalez-Rajal A, Dobarro D, Torroja C, Martinez F, Izquierdo-Garcia JL, Fernandez-Friera L, Sabater-Molina M, Kong YY, Pizarro G, Ibanez B, Medrano C, Garcia-Pavia P, Gimeno JR, Monserrat L, Jimenez-Borreguero LJ, de la Pompa JL (2013) Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 19(2):193–201CrossRefPubMedPubMedCentralGoogle Scholar
  250. MacGrogan D, Nus M, de la Pompa JL (2010) Notch signaling in cardiac development and disease. Curr Top Dev Biol 92:333–365CrossRefPubMedPubMedCentralGoogle Scholar
  251. Mahoney MB, Parks AL, Ruddy DA, Tiong SY, Esengil H, Phan AC, Philandrinos P, Winter CG, Chatterjee R, Huppert K, Fisher WW, L'Archeveque L, Mapa FA, Woo W, Ellis MC, Curtis D (2006) Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers. Genetics 172(4):2309–2324CrossRefPubMedPubMedCentralGoogle Scholar
  252. Mahoney-Sanchez L, Belaidi AA, Bush AI, Ayton S (2016) The complex role of apolipoprotein E in Alzheimer’s disease: an overview and update. J Mol Neurosci 60(3):325–335CrossRefPubMedPubMedCentralGoogle Scholar
  253. Maier D, Stumm G, Kuhn K, Preiss A (1992) Hairless, a Drosophila gene involved in neural development, encodes a novel, serine rich protein. Mech Dev 38(2):143–156CrossRefPubMedPubMedCentralGoogle Scholar
  254. Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, Boycott KM, Ste-Marie LG, McKiernan FE, Marik I, Van Esch H, Michaud JL, Samuels ME (2011) Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. Hum Mutat 32(10):1114–1117CrossRefPubMedGoogle Scholar
  255. Martignetti JA, Tian L, Li D, Ramirez MC, Camacho-Vanegas O, Camacho SC, Guo Y, Zand DJ, Bernstein AM, Masur SK, Kim CE, Otieno FG, Hou C, Abdel-Magid N, Tweddale B, Metry D, Fournet JC, Papp E, McPherson EW, Zabel C, Vaksmann G, Morisot C, Keating B, Sleiman PM, Cleveland JA, Everman DB, Zackai E, Hakonarson H (2013) Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet 92(6):1001–1007CrossRefPubMedPubMedCentralGoogle Scholar
  256. MARRVEL (2017) Scholar
  257. Mazaleyrat SL, Fostier M, Wilkin MB, Aslam H, Evans DA, Cornell M, Baron M (2003) Down-regulation of Notch target gene expression by Suppressor of deltex. Dev Biol 255(2):363–372CrossRefPubMedGoogle Scholar
  258. McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, Cole SE (2008) NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet 17(18):2886–2893CrossRefPubMedPubMedCentralGoogle Scholar
  259. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79(1):169–173CrossRefPubMedPubMedCentralGoogle Scholar
  260. McMillan BJ, Zimmerman B, Egan ED, Lofgren M, Xu X, Hesser A, Blacklow SC (2017) Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations. Glycobiology 27(8):777–786CrossRefPubMedPubMedCentralGoogle Scholar
  261. Meester JA, Southgate L, Stittrich AB, Venselaar H, Beekmans SJ, den Hollander N, Bijlsma EK, Helderman-van den Enden A, Verheij JB, Glusman G, Roach JC, Lehman A, Patel MS, de Vries BB, Ruivenkamp C, Itin P, Prescott K, Clarke S, Trembath R, Zenker M, Sukalo M, Van Laer L, Loeys B, Wuyts W (2015) Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome. Am J Hum Genet 97(3):475–482CrossRefPubMedPubMedCentralGoogle Scholar
  262. Micchelli CA, Rulifson EJ, Blair SS (1997) The function and regulation of cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate. Development 124(8):1485–1495PubMedGoogle Scholar
  263. Michel M, Aliee M, Rudolf K, Bialas L, Julicher F, Dahmann C (2016) The selector gene apterous and Notch are required to locally increase mechanical cell bond tension at the Drosophila dorsoventral compartment boundary. PLoS One 11(8):e0161668CrossRefPubMedPubMedCentralGoogle Scholar
  264. Michellod MA, Randsholt NB (2008) Implication of the Drosophila beta-amyloid peptide binding-like protein AMX in Notch signaling during early neurogenesis. Brain Res Bull 75(2-4):305–309CrossRefPubMedGoogle Scholar
  265. Mishra AK, Sachan N, Mutsuddi M, Mukherjee A (2015) Kinase active Misshapen regulates Notch signaling in Drosophila melanogaster. Exp Cell Res 339(1):51–60CrossRefPubMedGoogle Scholar
  266. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF (2000) Fringe is a glycosyltransferase that modifies Notch. Nature 406(6794):369–375CrossRefPubMedPubMedCentralGoogle Scholar
  267. Monet-Lepretre M, Bardot B, Lemaire B, Domenga V, Godin O, Dichgans M, Tournier-Lasserve E, Cohen-Tannoudji M, Chabriat H, Joutel A (2009) Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain 132(Pt 6):1601–1612CrossRefPubMedPubMedCentralGoogle Scholar
  268. Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F (2001) Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Curr Biol 11(10):789–792CrossRefPubMedGoogle Scholar
  269. Morgan TH, Sturtevant AH, Bridges CB (1922) Year B Carnegie Inst Wash 22:283–287Google Scholar
  270. Morrissette JD, Colliton RP, Spinner NB (2001) Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet 10(4):405–413CrossRefPubMedGoogle Scholar
  271. Moshkin YM, Kan TW, Goodfellow H, Bezstarosti K, Maeda RK, Pilyugin M, Karch F, Bray SJ, Demmers JA, Verrijzer CP (2009) Histone chaperones ASF1 and NAP1 differentially modulate removal of active histone marks by LID-RPD3 complexes during NOTCH silencing. Mol Cell 35(6):782–793CrossRefPubMedGoogle Scholar
  272. Mourikis P, Lake RJ, Firnhaber CB, DeDecker BS (2010) Modifiers of notch transcriptional activity identified by genome-wide RNAi. BMC Dev Biol 10:107CrossRefPubMedPubMedCentralGoogle Scholar
  273. Mouse Genome Informatics (2017)
  274. Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S (2005) Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7(12):1191–1201CrossRefPubMedGoogle Scholar
  275. Muller R, Jenny A, Stanley P (2013) The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila. PLoS One 8(5):e62835CrossRefPubMedPubMedCentralGoogle Scholar
  276. Mummery-Widmer JL, Yamazaki M, Stoeger T, Novatchkova M, Bhalerao S, Chen D, Dietzl G, Dickson BJ, Knoblich JA (2009) Genome-wide analysis of Notch signalling in Drosophila by transgenic RNAi. Nature 458(7241):987–992CrossRefPubMedPubMedCentralGoogle Scholar
  277. Nagarkar-Jaiswal S, DeLuca SZ, Lee PT, Lin WW, Pan H, Zuo Z, Lv J, Spradling AC, Bellen HJ (2015a) A genetic toolkit for tagging intronic MiMIC containing genes. elife 4:e08469PubMedCentralCrossRefGoogle Scholar
  278. Nagarkar-Jaiswal S, Lee PT, Campbell ME, Chen K, Anguiano-Zarate S, Gutierrez MC, Busby T, Lin WW, He Y, Schulze KL, Booth BW, Evans-Holm M, Venken KJ, Levis RW, Spradling AC, Hoskins RA, Bellen HJ (2015b) A library of MiMICs allows tagging of genes and reversible, spatial and temporal knockdown of proteins in Drosophila. elife 4:e05338PubMedCentralCrossRefGoogle Scholar
  279. Nagel AC, Krejci A, Tenin G, Bravo-Patino A, Bray S, Maier D, Preiss A (2005) Hairless-mediated repression of notch target genes requires the combined activity of Groucho and CtBP corepressors. Mol Cell Biol 25(23):10433–10441CrossRefPubMedPubMedCentralGoogle Scholar
  280. Nakao K, Campos-Ortega JA (1996) Persistent expression of genes of the enhancer of split complex suppresses neural development in Drosophila. Neuron 16(2):275–286CrossRefPubMedPubMedCentralGoogle Scholar
  281. Neumann CJ, Cohen SM (1997) Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124(4):871–880PubMedPubMedCentralGoogle Scholar
  282. Nguyen HT, Voza F, Ezzeddine N, Frasch M (2007) Drosophila mind bomb2 is required for maintaining muscle integrity and survival. J Cell Biol 179(2):219–227CrossRefPubMedPubMedCentralGoogle Scholar
  283. Nolo R, Abbott LA, Bellen HJ (2000) Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102(3):349–362CrossRefPubMedPubMedCentralGoogle Scholar
  284. Nowell C, Radtke F (2013) Cutaneous Notch signaling in health and disease. Cold Spring Harb Perspect Med 3(12):a017772CrossRefPubMedPubMedCentralGoogle Scholar
  285. Nus M, MacGrogan D, Martinez-Poveda B, Benito Y, Casanova JC, Fernandez-Aviles F, Bermejo J, de la Pompa JL (2011) Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arterioscler Thromb Vasc Biol 31(7):1580–1588CrossRefPubMedPubMedCentralGoogle Scholar
  286. O'Connor-Giles KM, Skeath JB (2003) Numb inhibits membrane localization of Sanpodo, a four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. Dev Cell 5(2):231–243CrossRefPubMedPubMedCentralGoogle Scholar
  287. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16(3):235–242CrossRefPubMedPubMedCentralGoogle Scholar
  288. Oellers N, Dehio M, Knust E (1994) bHLH proteins encoded by the Enhancer of split complex of Drosophila negatively interfere with transcriptional activation mediated by proneural genes. Mol Gen Genet 244(5):465–473CrossRefPubMedGoogle Scholar
  289. Okajima T, Irvine KD (2002) Regulation of notch signaling by o-linked fucose. Cell 111(6):893–904CrossRefPubMedGoogle Scholar
  290. Online Mendelian Inheritance in Man (2017)
  291. Opherk C, Duering M, Peters N, Karpinska A, Rosner S, Schneider E, Bader B, Giese A, Dichgans M (2009) CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet 18(15):2761–2767CrossRefPubMedGoogle Scholar
  292. Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U, Ludwig L, Wilda M, Hameister H, Knochel W, Liptay S, Schmid RM (2002) SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J 21(20):5417–5426CrossRefPubMedPubMedCentralGoogle Scholar
  293. Palmer WH, Deng WM (2015) Ligand-independent mechanisms of notch activity. Trends Cell Biol 25(11):697–707CrossRefPubMedPubMedCentralGoogle Scholar
  294. Panin VM, Papayannopoulos V, Wilson R, Irvine KD (1997) Fringe modulates Notch-ligand interactions. Nature 387(6636):908–912CrossRefPubMedGoogle Scholar
  295. Parks AL, Muskavitch MA (1993) Delta function is required for bristle organ determination and morphogenesis in Drosophila. Dev Biol 157(2):484–496CrossRefPubMedGoogle Scholar
  296. Parks AL, Turner FR, Muskavitch MA (1995) Relationships between complex Delta expression and the specification of retinal cell fates during Drosophila eye development. Mech Dev 50(2–3):201–216CrossRefPubMedGoogle Scholar
  297. Paroush Z, Finley RL Jr, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D (1994) Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Cell 79(5):805–815CrossRefPubMedGoogle Scholar
  298. Pavlopoulos E, Pitsouli C, Klueg KM, Muskavitch MA, Moschonas NK, Delidakis C (2001) neuralized Encodes a peripheral membrane protein involved in delta signaling and endocytosis. Dev Cell 1(6):807–816CrossRefPubMedGoogle Scholar
  299. Penton AL, Leonard LD, Spinner NB (2012) Notch signaling in human development and disease. Semin Cell Dev Biol 23(4):450–457CrossRefPubMedPubMedCentralGoogle Scholar
  300. Periz G, Fortini ME (1999) Ca(2+)-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila. EMBO J 18(21):5983–5993CrossRefPubMedPubMedCentralGoogle Scholar
  301. Perrimon N, Lanjuin A, Arnold C, Noll E (1996) Zygotic lethal mutations with maternal effect phenotypes in Drosophila melanogaster. II Loci on the second and third chromosomes identified by P-element-induced mutations. Genetics 144(4):1681–1692PubMedPubMedCentralGoogle Scholar
  302. Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M (2004) CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res 299(2):454–464CrossRefPubMedGoogle Scholar
  303. Pezeron G, Millen K, Boukhatmi H, Bray S (2014) Notch directly regulates the cell morphogenesis genes Reck, talin and trio in adult muscle progenitors. J Cell Sci 127(Pt 21):4634–4644CrossRefPubMedPubMedCentralGoogle Scholar
  304. Pi H, Huang YC, Chen IC, Lin CD, Yeh HF, Pai LM (2011) Identification of 11-amino acid peptides that disrupt Notch-mediated processes in Drosophila. J Biomed Sci 18:42CrossRefPubMedPubMedCentralGoogle Scholar
  305. Piccolo P, Attanasio S, Secco I, Sangermano R, Strisciuglio C, Limongelli G, Miele E, Mutarelli M, Banfi S, Nigro V, Pons T, Valencia A, Zentilin L, Campione S, Nardone G, Lynnes TC, Celestino-Soper PB, Spoonamore KG, D’Armiento FP, Giacca M, Staiano A, Vatta M, Collesi C, Brunetti-Pierri N (2017) MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrierlike gastropathy. Hum Mol Genet 26(1):33–43PubMedGoogle Scholar
  306. Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69(5):840–855CrossRefPubMedGoogle Scholar
  307. Pines MK, Housden BE, Bernard F, Bray SJ, Roper K (2010) The cytolinker Pigs is a direct target and a negative regulator of Notch signalling. Development 137(6):913–922CrossRefPubMedPubMedCentralGoogle Scholar
  308. Pink AE, Simpson MA, Desai N, Trembath RC, Barker JN (2013) gamma-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis. J Invest Dermatol 133(3):601–607CrossRefPubMedGoogle Scholar
  309. Pitsouli C, Delidakis C (2005) The interplay between DSL proteins and ubiquitin ligases in Notch signaling. Development 132(18):4041–4050CrossRefPubMedGoogle Scholar
  310. Plunkett CR (1926) The interaction of genetic and environmental factors in development. J Exp Zool 46:181–244CrossRefGoogle Scholar
  311. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342(8873):697–699CrossRefPubMedGoogle Scholar
  312. PomBase (2017) Scholar
  313. Poulson DF (1936) Chromosome deficiencies and embryonic development. Ph.D. thesis, California Institute of Technology, CA, USAGoogle Scholar
  314. Poulson DF (1937) Chromosomal deficiencies and the embryonic development of Drosophila melanogaster. Proc Natl Acad Sci U S A 23(3):133–137CrossRefPubMedPubMedCentralGoogle Scholar
  315. Pourquie O, Kusumi K (2001) When body segmentation goes wrong. Clin Genet 60(6):409–416CrossRefPubMedGoogle Scholar
  316. Psaty BM, O’Donnell CJ, Gudnason V, Lunetta KL, Folsom AR, Rotter JI, Uitterlinden AG, Harris TB, Witteman JC, Boerwinkle E (2009) Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet 2(1):73–80CrossRefPubMedPubMedCentralGoogle Scholar
  317. Rajan A, Tien AC, Haueter CM, Schulze KL, Bellen HJ (2009) The Arp2/3 complex and WASp are required for apical trafficking of Delta into microvilli during cell fate specification of sensory organ precursors. Nat Cell Biol 11(7):815–824CrossRefPubMedPubMedCentralGoogle Scholar
  318. Ramoni RB, Mulvihill JJ, Adams DR, Allard P, Ashley EA, Bernstein JA, Gahl WA, Hamid R, Loscalzo J, McCray AT, Shashi V, Tifft CJ, Wise AL (2017) The undiagnosed diseases network: accelerating discovery about health and disease. Am J Hum Genet 100(2):185–192CrossRefPubMedPubMedCentralGoogle Scholar
  319. Rana NA, Haltiwanger RS (2011) Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Curr Opin Struct Biol 21(5):583–589CrossRefPubMedPubMedCentralGoogle Scholar
  320. Ranganathan P, Weaver KL, Capobianco AJ (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer 11(5):338–351CrossRefPubMedGoogle Scholar
  321. Rat Genome Database (2017)
  322. Rauskolb C, Correia T, Irvine KD (1999) Fringe-dependent separation of dorsal and ventral cells in the Drosophila wing. Nature 401(6752):476–480CrossRefPubMedGoogle Scholar
  323. Reddy GV, Rodrigues V (1999) A glial cell arises from an additional division within the mechanosensory lineage during development of the microchaete on the Drosophila notum. Development 126(20):4617–4622PubMedGoogle Scholar
  324. Rhyu MS, Jan LY, Jan YN (1994) Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells. Cell 76(3):477–491CrossRefPubMedGoogle Scholar
  325. Roegiers F, Jan LY, Jan YN (2005) Regulation of membrane localization of Sanpodo by lethal giant larvae and neuralized in asymmetrically dividing cells of Drosophila sensory organs. Mol Biol Cell 16(8):3480–3487CrossRefPubMedPubMedCentralGoogle Scholar
  326. Rottgen G, Wagner T, Hinz U (1998) A genetic screen for elements of the network that regulates neurogenesis in Drosophila. Mol Gen Genet 257(4):442–451CrossRefPubMedGoogle Scholar
  327. Royet J, Bouwmeester T, Cohen SM (1998) Notchless encodes a novel WD40-repeat-containing protein that modulates Notch signaling activity. EMBO J 17(24):7351–7360CrossRefPubMedPubMedCentralGoogle Scholar
  328. Rulifson EJ, Blair SS (1995) Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila. Development 121(9):2813–2824PubMedGoogle Scholar
  329. Rullinkov G, Tamme R, Sarapuu A, Lauren J, Sepp M, Palm K, Timmusk T (2009) Neuralized-2: expression in human and rodents and interaction with Delta-like ligands. Biochem Biophys Res Commun 389(3):420–425CrossRefPubMedGoogle Scholar
  330. Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EM, Lesnik Oberstein SA (2014) Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn 14(5):593–603CrossRefPubMedGoogle Scholar
  331. Saccharomyces Genome Database (2017)
  332. Saj A, Arziman Z, Stempfle D, van Belle W, Sauder U, Horn T, Durrenberger M, Paro R, Boutros M, Merdes G (2010) A combined ex vivo and in vivo RNAi screen for notch regulators in Drosophila reveals an extensive notch interaction network. Dev Cell 18(5):862–876CrossRefPubMedGoogle Scholar
  333. Sakaidani Y, Ichiyanagi N, Saito C, Nomura T, Ito M, Nishio Y, Nadano D, Matsuda T, Furukawa K, Okajima T (2012) O-linked-N-acetylglucosamine modification of mammalian Notch receptors by an atypical O-GlcNAc transferase Eogt1. Biochem Biophys Res Commun 419(1):14–19CrossRefPubMedGoogle Scholar
  334. Saleh M, Kamath BM, Chitayat D (2016) Alagille syndrome: clinical perspectives. Appl Clin Genet 9:75–82CrossRefPubMedPubMedCentralGoogle Scholar
  335. Sandoval H, Yao CK, Chen K, Jaiswal M, Donti T, Lin YQ, Bayat V, Xiong B, Zhang K, David G, Charng WL, Yamamoto S, Duraine L, Graham BH, Bellen HJ (2014) Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production. Elife 3: e03558.Google Scholar
  336. Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S (1992) Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev 6(12B):2620–2634CrossRefPubMedGoogle Scholar
  337. Sasamura T, Sasaki N, Miyashita F, Nakao S, Ishikawa HO, Ito M, Kitagawa M, Harigaya K, Spana E, Bilder D, Perrimon N, Matsuno K (2003) neurotic, a novel maternal neurogenic gene, encodes an O-fucosyltransferase that is essential for Notch-Delta interactions. Development 130(20):4785–4795CrossRefPubMedGoogle Scholar
  338. Schneider M, Troost T, Grawe F, Martinez-Arias A, Klein T (2013) Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome. J Cell Sci 126(Pt 2):645–656CrossRefPubMedGoogle Scholar
  339. Schreiber SL, Preiss A, Nagel AC, Wech I, Maier D (2002) Genetic screen for modifiers of the rough eye phenotype resulting from overexpression of the Notch antagonist hairless in Drosophila. Genesis 33(3):141–152CrossRefPubMedGoogle Scholar
  340. Schrons H, Knust E, Campos-Ortega JA (1992) The Enhancer of split complex and adjacent genes in the 96F region of Drosophila melanogaster are required for segregation of neural and epidermal progenitor cells. Genetics 132(2):481–503PubMedPubMedCentralGoogle Scholar
  341. Schwanbeck R (2015) The role of epigenetic mechanisms in Notch signaling during development. J Cell Physiol 230(5):969–981CrossRefPubMedGoogle Scholar
  342. Schweisguth F (2015) Asymmetric cell division in the Drosophila bristle lineage: from the polarization of sensory organ precursor cells to Notch-mediated binary fate decision. Wiley Interdiscip Rev Dev Biol 4(3):299–309CrossRefPubMedPubMedCentralGoogle Scholar
  343. Schweisguth F, Posakony JW (1992) Suppressor of Hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates. Cell 69(7):1199–1212CrossRefPubMedGoogle Scholar
  344. Seidner GA, Ye Y, Faraday MM, Alvord WG, Fortini ME (2006) Modeling clinically heterogeneous presenilin mutations with transgenic Drosophila. Curr Biol 16(10):1026–1033CrossRefPubMedGoogle Scholar
  345. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6):595–608CrossRefPubMedPubMedCentralGoogle Scholar
  346. Selva EM, Hong K, Baeg GH, Beverley SM, Turco SJ, Perrimon N, Hacker U (2001) Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat Cell Biol 3(9):809–815CrossRefPubMedGoogle Scholar
  347. Sethi MK, Buettner FF, Krylov VB, Takeuchi H, Nifantiev NE, Haltiwanger RS, Gerardy-Schahn R, Bakker H (2010) Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated notch epidermal growth factor repeats. J Biol Chem 285(3):1582–1586CrossRefPubMedGoogle Scholar
  348. Seugnet L, Simpson P, Haenlin M (1997) Requirement for dynamin during Notch signaling in Drosophila neurogenesis. Dev Biol 192(2):585–598CrossRefPubMedGoogle Scholar
  349. Shalaby NA, Parks AL, Morreale EJ, Osswalt MC, Pfau KM, Pierce EL, Muskavitch MA (2009) A screen for modifiers of notch signaling uncovers Amun, a protein with a critical role in sensory organ development. Genetics 182(4):1061–1076CrossRefPubMedPubMedCentralGoogle Scholar
  350. Shannon MP (1972) Characterization of the female-sterile mutant almondex of Drosophila melanogaster. Genetica 43(2):244–256CrossRefPubMedGoogle Scholar
  351. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375(6534):754–760CrossRefPubMedGoogle Scholar
  352. Shimizu H, Woodcock SA, Wilkin MB, Trubenova B, Monk NA, Baron M (2014) Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 157(5):1160–1174CrossRefPubMedPubMedCentralGoogle Scholar
  353. Siman R, Reaume AG, Savage MJ, Trusko S, Lin YG, Scott RW, Flood DG (2000) Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci 20(23):8717–8726CrossRefPubMedGoogle Scholar
  354. Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC (2011) Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet 43(4):303–305CrossRefPubMedGoogle Scholar
  355. Skalska L, Stojnic R, Li J, Fischer B, Cerda-Moya G, Sakai H, Tajbakhsh S, Russell S, Adryan B, Bray SJ (2015) Chromatin signatures at Notch-regulated enhancers reveal large-scale changes in H3K56ac upon activation. EMBO J 34(14):1889–1904CrossRefPubMedPubMedCentralGoogle Scholar
  356. Slaninova V, Krafcikova M, Perez-Gomez R, Steffal P, Trantirek L, Bray SJ, Krejci A (2016) Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle. Open Biol 6(2):150155CrossRefPubMedPubMedCentralGoogle Scholar
  357. Smoller D, Friedel C, Schmid A, Bettler D, Lam L, Yedvobnick B (1990) The Drosophila neurogenic locus mastermind encodes a nuclear protein unusually rich in amino acid homopolymers. Genes Dev 4(10):1688–1700CrossRefPubMedGoogle Scholar
  358. Solinger JA, Spang A (2013) Tethering complexes in the endocytic pathway: CORVET and HOPS. FEBS J 280(12):2743–2757CrossRefPubMedGoogle Scholar
  359. Southgate L, Sukalo M, Karountzos AS, Taylor EJ, Collinson CS, Ruddy D, Snape KM, Dallapiccola B, Tolmie JL, Joss S, Brancati F, Digilio MC, Graul-Neumann LM, Salviati L, Coerdt W, Jacquemin E, Wuyts W, Zenker M, Machado RD, Trembath RC (2015) Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies. Circ Cardiovasc Genet 8(4):572–581CrossRefPubMedPubMedCentralGoogle Scholar
  360. Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (2006) Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet 78(1):28–37CrossRefPubMedGoogle Scholar
  361. Sparrow DB, Guillen-Navarro E, Fatkin D, Dunwoodie SL (2008) Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Hum Mol Genet 17(23):3761–3766CrossRefPubMedGoogle Scholar
  362. Sparrow DB, Chapman G, Dunwoodie SL (2011) The mouse notches up another success: understanding the causes of human vertebral malformation. Mamm Genome 22(7-8):362–376CrossRefPubMedGoogle Scholar
  363. Sparrow DB, McInerney-Leo A, Gucev ZS, Gardiner B, Marshall M, Leo PJ, Chapman DL, Tasic V, Shishko A, Brown MA, Duncan EL, Dunwoodie SL (2013) Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Hum Mol Genet 22(8):1625–1631CrossRefPubMedGoogle Scholar
  364. Stanley P, Okajima T (2010) Roles of glycosylation in Notch signaling. Curr Top Dev Biol 92:131–164CrossRefPubMedGoogle Scholar
  365. Stifani S, Blaumueller CM, Redhead NJ, Hill RE, Artavanis-Tsakonas S (1992) Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins. Nat Genet 2(2):119–127CrossRefPubMedGoogle Scholar
  366. Stittrich AB, Lehman A, Bodian DL, Ashworth J, Zong Z, Li H, Lam P, Khromykh A, Iyer RK, Vockley JG, Baveja R, Silva ES, Dixon J, Leon EL, Solomon BD, Glusman G, Niederhuber JE, Roach JC, Patel MS (2014) Mutations in NOTCH1 cause Adams-Oliver syndrome. Am J Hum Genet 95(3):275–284CrossRefPubMedPubMedCentralGoogle Scholar
  367. Struhl G, Adachi A (2000) Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell 6(3):625–636CrossRefPubMedGoogle Scholar
  368. Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398(6727):522–525CrossRefPubMedGoogle Scholar
  369. Sun Y, Yan Y, Denef N, Schupbach T (2011) Regulation of somatic myosin activity by protein phosphatase 1beta controls Drosophila oocyte polarization. Development 138(10):1991–2001CrossRefPubMedPubMedCentralGoogle Scholar
  370. Tada M, Itoh S, Ishii-Watabe A, Suzuki T, Kawasaki N (2012) Functional analysis of the Notch ligand Jagged1 missense mutant proteins underlying Alagille syndrome. FEBS J 279(12):2096–2107CrossRefPubMedPubMedCentralGoogle Scholar
  371. Tagami S, Okochi M, Yanagida K, Ikuta A, Fukumori A, Matsumoto N, Ishizuka-Katsura Y, Nakayama T, Itoh N, Jiang J, Nishitomi K, Kamino K, Morihara T, Hashimoto R, Tanaka T, Kudo T, Chiba S, Takeda M (2008) Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol Cell Biol 28(1):165–176CrossRefPubMedPubMedCentralGoogle Scholar
  372. Takats S, Pircs K, Nagy P, Varga A, Karpati M, Hegedus K, Kramer H, Kovacs AL, Sass M, Juhasz G (2014) Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila. Mol Biol Cell 25(8):1338–1354CrossRefPubMedPubMedCentralGoogle Scholar
  373. Takayama S, Dhahbi J, Roberts A, Mao G, Heo SJ, Pachter L, Martin DI, Boffelli D (2014) Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome Res 24(5):821–830CrossRefPubMedPubMedCentralGoogle Scholar
  374. Taniguchi Y, Furukawa T, Tun T, Han H, Honjo T (1998) LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol Cell Biol 18(1):644–654CrossRefPubMedPubMedCentralGoogle Scholar
  375. Tao J, Chen S, Lee B (2010) Alteration of Notch signaling in skeletal development and disease. Ann N Y Acad Sci 1192:257–268CrossRefPubMedPubMedCentralGoogle Scholar
  376. Teider N, Scott DK, Neiss A, Weeraratne SD, Amani VM, Wang Y, Marquez VE, Cho YJ, Pomeroy SL (2010) Neuralized1 causes apoptosis and downregulates Notch target genes in medulloblastoma. Neuro-Oncology 12(12):1244–1256CrossRefPubMedPubMedCentralGoogle Scholar
  377. Terriente-Felix A, Li J, Collins S, Mulligan A, Reekie I, Bernard F, Krejci A, Bray S (2013) Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme. Development 140(4):926–937CrossRefPubMedPubMedCentralGoogle Scholar
  378. Thomas U, Speicher SA, Knust E (1991) The Drosophila gene Serrate encodes an EGF-like transmembrane protein with a complex expression pattern in embryos and wing discs. Development 111(3):749–761PubMedGoogle Scholar
  379. Tian X, Hansen D, Schedl T, Skeath JB (2004) Epsin potentiates Notch pathway activity in Drosophila and C. elegans. Development 131(23):5807–5815CrossRefPubMedGoogle Scholar
  380. Tien AC, Rajan A, Schulze KL, Ryoo HD, Acar M, Steller H, Bellen HJ (2008) Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster. J Cell Biol 182(6):1113–1125CrossRefPubMedPubMedCentralGoogle Scholar
  381. Troost T, Jaeckel S, Ohlenhard N, Klein T (2012) The tumour suppressor Lethal (2) giant discs is required for the function of the ESCRT-III component Shrub/CHMP4. J Cell Sci 125(Pt 3):763–776CrossRefPubMedGoogle Scholar
  382. Troost T, Schneider M, Klein T (2015) A re-examination of the selection of the sensory organ precursor of the bristle sensilla of Drosophila melanogaster. PLoS Genet 11(1):e1004911CrossRefPubMedPubMedCentralGoogle Scholar
  383. Udolph G (2012) Notch signaling and the generation of cell diversity in Drosophila neuroblast lineages. Adv Exp Med Biol 727:47–60CrossRefPubMedGoogle Scholar
  384. Vaccari T, Bilder D (2005) The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev Cell 9(5):687–698CrossRefPubMedGoogle Scholar
  385. Vaccari T, Lu H, Kanwar R, Fortini ME, Bilder D (2008) Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. J Cell Biol 180(4):755–762CrossRefPubMedPubMedCentralGoogle Scholar
  386. Vaccari T, Rusten TE, Menut L, Nezis IP, Brech A, Stenmark H, Bilder D (2009) Comparative analysis of ESCRT-I, ESCRT-II and ESCRT-III function in Drosophila by efficient isolation of ESCRT mutants. J Cell Sci 122(Pt 14):2413–2423CrossRefPubMedPubMedCentralGoogle Scholar
  387. Vaccari T, Duchi S, Cortese K, Tacchetti C, Bilder D (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137(11):1825–1832CrossRefPubMedPubMedCentralGoogle Scholar
  388. Vallejo DM, Caparros E, Dominguez M (2011) Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells. EMBO J 30(4):756–769CrossRefPubMedPubMedCentralGoogle Scholar
  389. van de Hoef DL, Hughes J, Livne-Bar I, Garza D, Konsolaki M, Boulianne GL (2009) Identifying genes that interact with Drosophila presenilin and amyloid precursor protein. Genesis 47(4):246–260CrossRefPubMedGoogle Scholar
  390. Vassin H, Bremer KA, Knust E, Campos-Ortega JA (1987) The neurogenic gene Delta of Drosophila melanogaster is expressed in neurogenic territories and encodes a putative transmembrane protein with EGF-like repeats. EMBO J 6(11):3431–3440PubMedPubMedCentralCrossRefGoogle Scholar
  391. Venken KJ, Schulze KL, Haelterman NA, Pan H, He Y, Evans-Holm M, Carlson JW, Levis RW, Spradling AC, Hoskins RA, Bellen HJ (2011) MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes. Nat Methods 8(9):737–743CrossRefPubMedPubMedCentralGoogle Scholar
  392. Verheyen EM, Purcell KJ, Fortini ME, Artavanis-Tsakonas S (1996) Analysis of dominant enhancers and suppressors of activated Notch in Drosophila. Genetics 144(3):1127–1141PubMedPubMedCentralGoogle Scholar
  393. Veugelen S, Saito T, Saido TC, Chavez-Gutierrez L, De Strooper B (2016) Familial Alzheimer’s disease mutations in presenilin generate amyloidogenic abeta peptide seeds. Neuron 90(2):410–416CrossRefPubMedGoogle Scholar
  394. Vienna Drosophila Resource Center (2017)
  395. Wahi K, Bochter MS, Cole SE (2016) The many roles of Notch signaling during vertebrate somitogenesis. Semin Cell Dev Biol 49:68–75CrossRefPubMedGoogle Scholar
  396. Wang W, Struhl G (2005) Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila. Development 132(12):2883–2894CrossRefPubMedGoogle Scholar
  397. Wang S, Tan KL, Agosto MA, Xiong B, Yamamoto S, Sandoval H, Jaiswal M, Bayat V, Zhang K, Charng WL, David G, Duraine L, Venkatachalam K, Wensel TG, Bellen HJ (2015) The retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration. PLoS Biol 12(4):e1001847CrossRefGoogle Scholar
  398. Wang J, Al-Ouran R, Hu Y, Kim SY, Wan YW, Wangler MF, Yamamoto S, Chao HT, Comjean A, Mohr SE, Udn PN, Liu Z, Bellen HJ (2017) MARRVEL: integration of human and model organism genetic resources to facilitate functional annotation of the human genome. Am J Hum Genet 100(6):843–853CrossRefPubMedPubMedCentralGoogle Scholar
  399. Wangler MF, Yamamoto S, Bellen HJ (2015) Fruit flies in biomedical research. Genetics 199(3):639–653CrossRefPubMedPubMedCentralGoogle Scholar
  400. Wangler MF, Hu Y, Shulman JM (2017) Drosophila and genome-wide association studies: a review and resource for the functional dissection of human complex traits. Dis Model Mech 10(2):77–88CrossRefPubMedPubMedCentralGoogle Scholar
  401. Weber D, Wiese C, Gessler M (2014) Hey bHLH transcription factors. Curr Top Dev Biol 110:285–315CrossRefPubMedGoogle Scholar
  402. Weinmaster G, Fischer JA (2011) Notch ligand ubiquitylation: what is it good for? Dev Cell 21(1):134–144CrossRefPubMedPubMedCentralGoogle Scholar
  403. Welshons WJ (1956) Dosage experiments with split mutants in the presence of an enhancer of split. Drosophila Inf Serv 30:157–158Google Scholar
  404. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43(3 Pt 2):567–581CrossRefPubMedGoogle Scholar
  405. White PH, Farkas DR, Chapman DL (2005) Regulation of Tbx6 expression by Notch signaling. Genesis 42(2):61–70CrossRefPubMedGoogle Scholar
  406. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL, Turnpenny PD (2004) Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet 74(6):1249–1254CrossRefPubMedPubMedCentralGoogle Scholar
  407. Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K, Hori K, Taniguchi-Kanai M, Franklin E, Matsuno K, Baron M (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway. Dev Cell 15(5):762–772CrossRefPubMedGoogle Scholar
  408. Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG (2009) Alzheimer’s disease and Notch signaling. Biochem Biophys Res Commun 390(4):1093–1097CrossRefPubMedGoogle Scholar
  409. WormBase (2017) Scholar
  410. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD (2002) Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol 22(21):7688–7700CrossRefPubMedPubMedCentralGoogle Scholar
  411. Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, Shen Y, Yu G, Liu J, Xie H, Gucev ZS, Liu S, Yang N, Al-Kateb H, Chen J, Zhang J, Hauser N, Zhang T, Tasic V, Liu P, Su X, Pan X, Liu C, Wang L, Shen J, Shen J, Chen Y, Zhang T, Zhang J, Choy KW, Wang J, Wang Q, Li S, Zhou W, Guo J, Wang Y, Zhang C, Zhao H, An Y, Zhao Y, Wang J, Liu Z, Zuo Y, Tian Y, Weng X, Sutton VR, Wang H, Ming Y, Kulkarni S, Zhong TP, Giampietro PF, Dunwoodie SL, Cheung SW, Zhang X, Jin L, Lupski JR, Qiu G, Zhang F (2015) TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med 372(4):341–350CrossRefPubMedPubMedCentralGoogle Scholar
  412. Wurmbach E, Wech I, Preiss A (1999) The Enhancer of split complex of Drosophila melanogaster harbors three classes of Notch responsive genes. Mech Dev 80(2):171–180CrossRefPubMedGoogle Scholar
  413. Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ 3rd (2015) Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 85(5):967–981CrossRefPubMedPubMedCentralGoogle Scholar
  414. Xia D, Kelleher RJ 3rd, Shen J (2016) Loss of Abeta43 production caused by Presenilin-1 mutations in the Knockin mouse brain. Neuron 90(2):417–422CrossRefPubMedPubMedCentralGoogle Scholar
  415. Xie T, Song X, Jin Z, Pan L, Weng C, Chen S, Zhang N (2008) Interactions between stem cells and their niche in the Drosophila ovary. Cold Spring Harb Symp Quant Biol 73:39–47CrossRefPubMedGoogle Scholar
  416. Xiong B, Bayat V, Jaiswal M, Zhang K, Sandoval H, Charng WL, Li T, David G, Duraine L, Lin YQ, Neely GG, Yamamoto S, Bellen HJ (2012) Crag is a GEF for Rab11 required for rhodopsin trafficking and maintenance of adult photoreceptor cells. PLoS Biol 10(12):e1001438CrossRefPubMedPubMedCentralGoogle Scholar
  417. Xu T, Artavanis-Tsakonas S (1990) deltex, a locus interacting with the neurogenic genes, Notch, Delta and mastermind in Drosophila melanogaster. Genetics 126(3):665–677PubMedPubMedCentralGoogle Scholar
  418. Xu T, Rubin GM (1993) Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117(4):1223–1237PubMedGoogle Scholar
  419. Xu A, Haines N, Dlugosz M, Rana NA, Takeuchi H, Haltiwanger RS, Irvine KD (2007) In vitro reconstitution of the modulation of Drosophila Notch-ligand binding by Fringe. J Biol Chem 282(48):35153–35162CrossRefPubMedGoogle Scholar
  420. Yamada K, Fuwa TJ, Ayukawa T, Tanaka T, Nakamura A, Wilkin MB, Baron M, Matsuno K (2011) Roles of Drosophila deltex in Notch receptor endocytic trafficking and activation. Genes Cells 16(3):261–272CrossRefPubMedGoogle Scholar
  421. Yamamoto S, Charng WL, Bellen HJ (2010) Endocytosis and intracellular trafficking of Notch and its ligands. Curr Top Dev Biol 92:165–200CrossRefPubMedGoogle Scholar
  422. Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwanger RS, Bellen HJ (2012) A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338(6111):1229–1232CrossRefPubMedPubMedCentralGoogle Scholar
  423. Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LE, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ (2014) A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell 159(1):200–214CrossRefPubMedPubMedCentralGoogle Scholar
  424. Yan Y, Denef N, Schupbach T (2009) The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell 17(3):387–402CrossRefPubMedPubMedCentralGoogle Scholar
  425. Yasuhiko Y, Haraguchi S, Kitajima S, Takahashi Y, Kanno J, Saga Y (2006) Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proc Natl Acad Sci U S A 103(10):3651–3656CrossRefPubMedPubMedCentralGoogle Scholar
  426. Ye Y, Lukinova N, Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398(6727):525–529CrossRefPubMedGoogle Scholar
  427. Yedvobnick B, Helms W, Barrett B (2001) Identification of chromosomal deficiencies that modify Drosophila mastermind mutant phenotypes. Genesis 30(4):250–258CrossRefPubMedGoogle Scholar
  428. Yochem J, Greenwald I (1989) glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell 58(3):553–563CrossRefPubMedGoogle Scholar
  429. Yochem J, Weston K, Greenwald I (1988) The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Nature 335(6190):547–550CrossRefPubMedGoogle Scholar
  430. Yoon WH, Sandoval H, Nagarkar-Jaiswal S, Jaiswal M, Yamamoto S, Haelterman NA, Putluri N, Putluri V, Sreekumar A, Tos T, Aksoy A, Donti T, Graham BH, Ohno M, Nishi E, Hunter J, Muzny DM, Carmichael J, Shen J, Arboleda VA, Nelson SF, Wangler MF, Karaca E, Lupski JR, Bellen HJ (2017) Loss of Nardilysin, a Mitochondrial Co-chaperone for alpha-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration. Neuron 93(1):115–131CrossRefPubMedGoogle Scholar
  431. Yu H, Takeuchi H, Takeuchi M, Liu Q, Kantharia J, Haltiwanger RS, Li H (2016) Structural analysis of Notch-regulating Rumi reveals basis for pathogenic mutations. Nat Chem Biol 12(9):735–740CrossRefPubMedPubMedCentralGoogle Scholar
  432. Yuan JS, Kousis PC, Suliman S, Visan I, Guidos CJ (2011) Functions of notch signaling in the immune system: consensus and controversies. Annu Rev Immunol 28:343–365CrossRefGoogle Scholar
  433. Yuan Z, Praxenthaler H, Tabaja N, Torella R, Preiss A, Maier D, Kovall RA (2016) Structure and function of the Su(H)-Hairless repressor complex, the major antagonist of notch signaling in Drosophila melanogaster. PLoS Biol 14(7):e1002509CrossRefPubMedPubMedCentralGoogle Scholar
  434. Zacharioudaki E, Housden BE, Garinis G, Stojnic R, Delidakis C, Bray SJ (2016) Genes implicated in stem cell identity and temporal programme are directly targeted by Notch in neuroblast tumours. Development 143(2):219–231CrossRefPubMedPubMedCentralGoogle Scholar
  435. Zanotti S, Canalis E (2010) Notch and the skeleton. Mol Cell Biol 30(4):886–896CrossRefPubMedGoogle Scholar
  436. Zebrafish Information Network (2017)
  437. Zecca M, Basler K, Struhl G (1996) Direct and long-range action of a wingless morphogen gradient. Cell 87(5):833–844CrossRefPubMedGoogle Scholar
  438. Zeng C, Younger-Shepherd S, Jan LY, Jan YN (1998) Delta and Serrate are redundant Notch ligands required for asymmetric cell divisions within the Drosophila sensory organ lineage. Genes Dev 12(8):1086–1091CrossRefPubMedPubMedCentralGoogle Scholar
  439. Zhang J, Liu M, Su Y, Du J, Zhu AJ (2012) A targeted in vivo RNAi screen reveals deubiquitinases as new regulators of Notch signaling. G3 (Bethesda) 2(12):1563–1575CrossRefGoogle Scholar
  440. Zhang K, Li Z, Jaiswal M, Bayat V, Xiong B, Sandoval H, Charng WL, David G, Haueter C, Yamamoto S, Graham BH, Bellen HJ (2013) The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. J Cell Biol 200(6):807–820CrossRefPubMedPubMedCentralGoogle Scholar
  441. Ziemer A, Tietze K, Knust E, Campos-Ortega JA (1988) Genetic analysis of enhancer of split, a locus involved in neurogenesis in Drosophila melanogaster. Genetics 119(1):63–74PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular and Human GeneticsBaylor College of Medicine (BCM)HoustonUSA
  2. 2.Program in Developmental Biology, BCMHoustonUSA
  3. 3.Department of Neuroscience, BCMHoustonUSA
  4. 4.Jan and Dan Duncan Neurological Research InstituteTexas Children’s HospitalHoustonUSA

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