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

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

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.

Keywords

Notch signaling Drosophila Mendelian diseases Functional genomics Translational research 

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

Notes

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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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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