Abstract
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.
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Abbreviations
- AD:
-
Alzheimer’s disease
- ADAM10 :
-
A Disintegrin and Metalloprotease 10
- AES:
-
Amino-terminal Enhancer of Split
- ago :
-
archipelago
- amx :
-
almondex
- AOS:
-
Adams-Oliver Syndrome
- AP-3:
-
Adaptor Protein-3
- Aph:
-
Anterior pharynx defective
- APOE :
-
APOlipoprotein E
- APP:
-
Amyloid Precursor Protein
- aPKC:
-
atypical Protein Kinase C
- ARHGAP31 :
-
Rho GTPase-activating protein 31
- Arp2/3:
-
Actin-related protein 2/3
- AS-C:
-
Achaete-Scute Complex
- BAC:
-
Bacterial Artificial Chromosome
- bib :
-
big brain
- BDSC:
-
Bloomington Drosophila Stock Center
- bHLH:
-
basic Helix-Loop-Helix
- C. elegans :
-
Caenorhabditis elegans
- CADASIL:
-
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
- CBP/CREBBP:
-
C-Adenosine Mono Phosphate Responsive Element (cAMP-RE)-Binding protein (CREB)-Binding Protein
- CDK8 :
-
Cyclin-Dependent Kinase 8
- CREB:
-
cAMP response element binding protein
- cDNA:
-
complementary DeoxyriboNucleic Acid
- CHARGE:
-
Cohorts for Heart and Aging Research in Genomic Epidemiology
- CRISPR:
-
Clustered Regularly Interspaced Short Palindromic Repeats
- CtBP:
-
C-terminal Binding Protein
- DECHIPHER:
-
DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources
- DFS:
-
Dominant Female Sterile
- DGGR:
-
Drosophila Genomics and Genetic Resources
- DGRC:
-
Drosophila Genomics Resource Center
- DIOPT:
-
Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool
- Dl :
-
Delta
- DLL:
-
DeLta-Like
- DOCK6 :
-
Dedicator Of Cytokinesis 6
- DSHB:
-
Developmental Studies Hybridoma Bank
- dx :
-
deltex
- E(spl)-C :
-
Enhancer of split-Complex
- EGF:
-
Epidermal Growth Factor
- EHBP-1 :
-
EH (Eps15 Homology) domain Binding Protein-1
- elav :
-
embryonic lethal abnormal vision
- EMS:
-
Ethyl MethaneSulfonate
- Eogt :
-
EGF-domain O-GlcNAc transferase
- EP300 :
-
E1A binding protein P300
- ER:
-
Endoplasmic Reticulum
- ESCRT:
-
Endosomal Sorting Complex Required for Transport
- FAD:
-
Familial Alzheimer’s Disease
- FBXW7 :
-
F-BoX and WD repeat domain containing 7
- FHL1 :
-
Four and a Half LIM domains 1
- FLP:
-
FLiPpase
- Fng :
-
Fringe
- FRT:
-
Flippase Recognition Target
- GAP:
-
GTPase-Activating Protein
- GEF:
-
Guanine nucleotide Exchange Factor
- Geno2MP:
-
Genotype to Mendelian Phenotype Browser
- GFI1:
-
Growth Factor Independent 1 transcriptional repressor
- glcNAc:
-
N-Acetylglucosamine
- glp-1 :
-
abnormal germ line proliferation-1
- GOM:
-
Granular Osmophilic Material
- Gro :
-
Groucho
- GWAS:
-
Genome-Wide Association Studies
- H :
-
Hairless
- hAPF:
-
hours After Puparium Formation
- HCOP:
-
Human genome organization gene nomenclature committee Comparison of Orthology Predictions search
- HDR:
-
Homology Directed Repair
- HES:
-
Hairy and Enhancer of Split
- HEY:
-
Hairy/Enhancer-of-split related with YRPW motif
- HOPS:
-
HOmotypic fusion and Protein Sorting
- IMF:
-
Infantile MyoFibromatosis
- JAG:
-
JAGged
- kuz :
-
kuzbanian
- l(2)gd1 :
-
lethal (2) giant discs 1
- LFNG :
-
Lunatic FriNGe
- LIM :
-
Lin11, Isl-1 and Mec-3
- lin-12 :
-
cell lineage defective-12
- LMNS:
-
Lateral MeNingocele Syndrome
- LNR:
-
Lin-12/Notch Repeat
- LOAD:
-
Late-Onset Alzheimer’s Disease
- LVNC:
-
Left Ventricular NonCompaction
- mam :
-
mastermind
- MAML:
-
MAsterMind-Like
- MARRVEL:
-
Model organism Aggregated Resources for Rare Variant ExpLoration
- MESP2 :
-
Mesoderm posterior bHLH transcription factor 2
- MFNG :
-
Manic FriNGe
- MGI:
-
Mouse Genome Informatics
- mib:
-
mindbomb
- MiMIC:
-
Minos-Mediated Integration Cassette
- mRNA:
-
messenger RiboNucleic Acid
- Nct/NCSTN :
-
Nicastrin
- nej :
-
nejire
- neur/NEURL :
-
neuralized
- NEXT:
-
Notch EXtracellular Truncation
- NICD:
-
Notch IntraCellular Domain
- NRR:
-
Negative Regulatory Region
- O-fut1 :
-
O-fucosyltransferase-1
- OMIM:
-
Online Mendelian Inheritance in Man
- PDGFRB :
-
Platelet Derived Growth Factor Receptor Beta
- pen/PSENEN :
-
presenilin enhancer
- PEST:
-
proline (P), glutamic acid (E), serine (S) and threonine (T)-rich
- POFUT1 :
-
Protein O-fucosyltransferase 1
- POGLUT1 :
-
Protein O-glucosyltransferase 1
- PTM:
-
Post-Translational Modification
- Psn/PSEN :
-
Presenilin
- RBPJ :
-
Recombination signal Binding Protein for immunoglobulin kappa J region
- RFNG :
-
Radical FriNGe
- RIPPLY2 :
-
RIPPLY transcriptional repressor 2
- RMCE:
-
Recombinase Mediated Cassette Exchange
- RNAi:
-
RNA interference
- SA:
-
Splice Acceptor
- SCDO:
-
SpondyloCostal DysOstosis
- Sec15 :
-
Secretory 15
- Ser :
-
Serrate
- SGD:
-
Saccharomyces Genome Database
- SHARP:
-
SMRT/HDAC1 Associated Repressor Protein
- shi :
-
shibire
- SOP:
-
Sensory Organ Precursor
- spdo :
-
sanpodo
- SPEN :
-
SPlit ENds family transcriptional repressor
- spl :
-
split
- Su(dx) :
-
Suppressor of deltex
- Su(H) :
-
Suppressor of Hairless
- TBX6 :
-
T-BoX 6
- Temp :
-
Tempura
- TLE:
-
Transducin Like Enhancer protein
- TM2D3 :
-
TM2 Domain containing 3
- UAS:
-
Upstream Activation Sequence
- V-ATPase:
-
Vacuolar-Adenosine TriPhos-phatase
- VDRC:
-
Vienna Drosophila Resource Center
- VUS:
-
Variant of Unknown Significance
- WASp:
-
Wiskott-Aldrich Syndrome protein
- wg :
-
wingless
- ZFIN:
-
ZebraFish Information Network
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Acknowledgements
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).
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Salazar, J.L., Yamamoto, S. (2018). Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases. In: Borggrefe, T., Giaimo, B. (eds) Molecular Mechanisms of Notch Signaling. Advances in Experimental Medicine and Biology, vol 1066. Springer, Cham. https://doi.org/10.1007/978-3-319-89512-3_8
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