Table Of ContentCURRENT TOPICS IN
DEVELOPMENTAL BIOLOGY
“Ameeting-groundforcriticalreviewanddiscussionofdevelopmentalprocesses”
A.A.MosconaandAlbertoMonroy(Volume1,1966)
SERIES EDITOR
Paul M. Wassarman
Department ofDevelopmental andRegenerative Biology
IcahnSchool ofMedicine atMount Sinai
New York, NY,USA
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FOUNDING EDITORS
A.A. Moscona and Alberto Monroy
FOUNDING ADVISORY BOARD
Vincent G. Allfrey Dame Honor B.Fell
Jean Brachet John C. Kendrew
Seymour S. Cohen S.Spiegelman
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CONTRIBUTORS
H.J.Bellen
BaylorCollegeofMedicine;JanandDanDuncanNeurologicalResearchInstitute,Texas
Children’sHospital;PrograminDevelopmentalBiology;HowardHughesMedicalInstitute,
Houston,TX,UnitedStates
P.Bergman
ClinicalMicrobiologyF68,KarolinskaInstitutet,KarolinskaUniversityHospital,Huddinge,
Stockholm,Sweden
C.Burke
NeurologyResearch,Biogen,Cambridge,MA,UnitedStates
R.L.Cagan
IcahnSchoolofMedicineatMountSinai,NewYork,NY,UnitedStates
L.Chakravarti
PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA,
UnitedStates
R.T.Cox
UniformedServicesUniversity,Bethesda,MD,UnitedStates
J.M.I.Daenzer
EmoryUniversitySchoolofMedicine,Atlanta,GA,UnitedStates
Y.Engstro€m
TheWenner-GrenInstitute,StockholmUniversity,Stockholm,Sweden
J.L.Fridovich-Keil
EmoryUniversitySchoolofMedicine,Atlanta,GA,UnitedStates
D.C.I.Goberdhan
UniversityofOxford,Oxford,UnitedKingdom
P.Graham
UniversityofMaryland,CollegePark,MD,UnitedStates
F.Hamdy
UniversityofOxford,JohnRadcliffeHospital,Oxford,UnitedKingdom
V.L.Hewitt
MedicalResearchCouncilMitochondrialBiologyUnit,Cambridge,UnitedKingdom
S.X.Hou
TheBasicResearchLaboratory,NationalCancerInstituteatFrederick,NationalInstitutesof
Health,Frederick,MD,UnitedStates
xi
xii Contributors
M.S.Kayser
PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA,
UnitedStates
R.E.Kreipke
UniversityofWashington;InstituteforStemCellandRegenerativeMedicine,Schoolof
Medicine,Seattle,WA,UnitedStates
M.Krench
ThePicowerInstituteforLearningandMemory,MassachusettsInstituteofTechnology,
Cambridge,MA,UnitedStates
Y.V.Kwon
UniversityofWashington,SchoolofMedicine,Seattle,WA,UnitedStates
A.Leiblich
UniversityofOxford;JohnRadcliffeHospital,Oxford,UnitedKingdom
G.Lin
BaylorCollegeofMedicine;JanandDanDuncanNeurologicalResearchInstitute,Texas
Children’sHospital,Houston,TX,UnitedStates
J.T.Littleton
ThePicowerInstituteforLearningandMemory,MassachusettsInstituteofTechnology,
Cambridge,MA,UnitedStates
D.Mao
JanandDanDuncanNeurologicalResearchInstitute,TexasChildren’sHospital;Programin
DevelopmentalBiology,BaylorCollegeofMedicine,Houston,TX,UnitedStates
E.H.Moscato
PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA,
UnitedStates
V.Nadar
NeurologyResearch,Biogen,Cambridge,MA,UnitedStates
L.Pick
UniversityofMaryland,CollegePark,MD,UnitedStates
H.Ruohola-Baker
UniversityofWashington;InstituteforStemCellandRegenerativeMedicine,Schoolof
Medicine,Seattle,WA,UnitedStates
S.Sanyal
NeurologyResearch,Biogen,Cambridge,MA,UnitedStates
A.Sen
UniformedServicesUniversity,Bethesda,MD,UnitedStates
S.SeyedoleslamiEsfahani
TheWenner-GrenInstitute,StockholmUniversity,Stockholm,Sweden
Contributors xiii
H.R.Shcherbata
MaxPlanckResearchGroupofGeneExpressionandSignaling,MaxPlanckInstitutefor
BiophysicalChemistry,Go€ttingen,Germany
S.R.Singh
TheBasicResearchLaboratory,NationalCancerInstituteatFrederick,NationalInstitutesof
Health,Frederick,MD,UnitedStates
M.Sonoshita
IcahnSchoolofMedicineatMountSinai,NewYork,NY,UnitedStates;KyotoUniversity
GraduateSchoolofMedicine,Kyoto,Japan
K.Trinh
NeurologyResearch,Biogen,Cambridge,MA,UnitedStates
A.J.Whitworth
MedicalResearchCouncilMitochondrialBiologyUnit,Cambridge,UnitedKingdom
C.Wilson
UniversityofOxford,Oxford,UnitedKingdom
PREFACE
The fruit fly, Drosophila melanogaster, is arguably the most sophisticated
model organism developed to date. With over a hundred years of genetics
andthousandsofresearchersworldwide,toolstostudygeneexpressionand
function—fromdetailedmolecularanalysisofsinglegenestogenome-wide
analysesofregulatoryphenomena—areavailableatanunprecedentedscale.
Results are shared freely among Drosophila researchers through informa-
tional databases and repositories such as FlyBase, collections such as the
Bloomington Stock Center that distributes fly lines at a minimal cost, and
thehistoriccollegialnatureofinteractionamongflyresearchers.Inaddition
tobothpastandongoingcontributionstobasicresearchinalmosteveryarea
of science, Drosophila has now been established as a model to study human
disease.Withorthologsofmorethan60%ofhumandisease-causinggenes,
often present in single copy in flies but duplicated in vertebrates, and the
wealth of tools available to assess gene function, genetic interactions, and
environmentalinfluences,Drosophilaisanidealsystemforelucidatingmech-
anisms underlying pathologies. This special volume provides examples of
someofthebest-developedflymodelsforavarietyofhumandiseases.Many
of these affect the nervous system, but the types of diseases that have been
effectivelymodeledspanabroadrange,frommetabolicdisorderstocancer
to bacterial infections. In each chapter, the basic pathologies in human
patients and the parallels to Drosophila biology are discussed. The strengths
of Drosophila as a model are presented, as well as weaknesses of its use as a
model system, important to keep in mind for accurate translation to the
human condition.
Mitochondrialdiseasesareauniqueandcomplexsetofdiseasesthatare
maternallyinheritedanddifficulttodiagnoseandtreat.SenandCoxreview
theuseofDrosophilatostudymitochondrialdiseaseandmitochondrialinheritance.
They review existing fly models for several mitochondrial diseases and
methodology available in the fly to generate targeted mutations in
mitochondrial DNA. Finally, they discuss recent findings on the role of
mitochondrial purification during oogenesis and experiments in Drosophila
that are unraveling how this is achieved.
Whileinsectsdonothaveadaptiveimmunesystems,theysharewithver-
tebrates an innate immune system. In fact, much of our understanding of
innateimmunitycomesfromDrosophilaresearch.AsreviewedbyBergman,
xv
xvi Preface
Esfahani, and Engstro€m, flies and humans also share microbial flora that
influencehealth.Studiesofhost–microbeinteractions,whichincludeshared
intracellularsignalingpathwaysandeffectormechanisms,arerevealingbasic
mechanisms utilized by animals to both protect against microbial invasion
and to promote the growth of a healthy microbiome.
Ruohola-Baker and coworkers present a discussion of contributions
made using Drosophila to study pathophysiological mechanisms underlying
muscledegenerativedisorders,includingDuchennemusculardystrophyandspi-
nal muscular atrophy, as well as muscle wasting seen in cancer and other
human disease. They point to genetic interaction screens in flies that have
identified pathways which could be targeted for therapeutic intervention
in these and other muscular diseases.
A number of chapters focus on the use of Drosophila to study neuronal
disease.Lin,Mao,andBellenfocusononedevastatingdisease,amyotrophic
lateral sclerosis (ALS). A number of genes have been implicated in familial
ALS and, given their conservation, Drosophila provides a model to study
their mechanisms of action. The authors propose that defects in RNA
andproteinhomeostasisbuilduponeachothertocauseaccumulatingpro-
teinaggregationthatispathologicalinALS.Resultstodateimplicateabnor-
malities in pre-mRNA splicing, protein folding, ER stress, proteasomal
degradation,andproteinmislocalizationasunderlyingbasesfordisease.This
review highlights the use of Drosophila as an assay system to uncover the
functionofgenesassociatedwithdiseaseinhumanstudies,andthepotential
the fly system has to reveal mechanism of action of mutations found in
human patients.
Hewitt and Whitworth similarly focus on a single neurodegenerative
disease, Parkinson’s disease (PD). Interactions between and mechanism of
actionofseveralgenesassociatedwithandcausalforPDhavebeenstudied
in Drosophila. Among others, the authors discuss the role of parkin in regu-
lating mitochondrial dynamics, a mechanism first elucidated in studies in
Drosophila.KrenchandLittletondiscussusingfliestostudythemechanisms
underlying neurodegenerative disorders associated with expanded poly-
glutamine tracts, such as Huntington’s diseases. They highlight progress
made using Drosophila models to explain the underlying basis of disease
andsuggestapproachestousingthesemodelstoidentifyandassesstherapies,
including genetic suppressor screens that have the power to both dissect
genetic interactions and identify potential drug targets.
Sanyalandcoworkerstakeaslightlydifferentapproachtodiscussingneu-
rodegenerative diseases, such as PD, by reviewing the importance of
Preface xvii
interactions between genes, age, and environment in disease onset and
progression. They look toward future “intersectional experiments” that
combine genetic approaches in the fly model with systems biology and
“omics” to reveal complex interactions that lead to full-blown disease.
Whilehighlightingmanystrengthsofferedbyflygenetics,theyalsoremind
thereaderabouttheneedfordeeperunderstandingofthemolecularbasisof
cellular defects before extrapolation to the human condition based upon
grossly similar phenotypes.
One of the more unexpected areas of fly research that proved to effec-
tivelymodelhumanconditionsissleepresearch.Thisareaexplodedinrecent
yearswiththeidentificationofgenesimpactingcircadianrhythmsandsleep
activity in flies. Kayser and coworkers review studies of specific regions of
the brain, neuronal circuitry, and signaling pathways that are highly con-
served between flies and humans that play roles in sleep–wake cycles,
responsetodeprivation,caffeine,andotherstimulants,impactingsleeppat-
ternsaswellaslearningandmemory.Theypointtoearlystudiesinthisfield
that identified the period (per) mutation in flies—a gene later implicated in
human sleep disorders, and describe additional fly mutants that effectively
model human neurodevelopmental, psychiatric, and sleep disorders.
Drosophila has served as an excellent model for studies of cancer, as flies
harbor similar oncogenes and tumor suppressor genes to humans, and
mutationsresultinovergrowthandmetastasis,similartothatseeninhuman
disease.SonoshitaandCaganreviewtheidentificationofgenesresponsible
for overgrowth in Drosophila, which contributed to the finding that loss of
cell polarity is a key feature of malignancy. They give examples of genes
identifiedinDrosophilathroughgeneticmodifierscreensthatcanbeplaced
inorderedpathwaysusingflygenetics,providinginsightintomechanismsof
action.Theynextreviewmodelsofdifferenttypesofcancerthathavebeen
developedinfliesandhighlightinteractionsbetweendietandgenotypethat
are likely to prove important for cancer treatment. Finally, these authors
emphasize the potential of Drosophila for drug screening in whole animals,
citing,amongothers,thecontributionofaDrosophilamodeltotheapproval
ofvandetanibasatargetedtherapyforhumanpatients,andprojectsunder-
way to use fly models expressing specific oncogenes to test new, rationally
designed chemistries.
The role of stem cells in cancer is a major focus of recent research.
Drosophila is a particularly good model here, not only because of the pow-
erful genetics and numerous classes of identified stem cell lineages, but
becausetherearenoregulatoryissuesconstrainingresearch.HouandSingh
xviii Preface
review a number of recent findings on the role of stem cells in tumor for-
mationandprogressionindifferentstemcellpopulationsinDrosophila.They
discusstherolesofsignalingmoleculesandpathways,providingexamplesof
howDrosophilaresearchhascontributedtoourunderstandingofhowstem
cell tumors initiate and propagate. They discuss molecular differences
between normal and tumorigenic stem cells, and resistance of stem cells
to standard therapies. Wilson and coworkers focus on a specific cancer
type—prostate cancer—and ways in which the Drosophila accessory gland
has been used to model this disease. They highlight the rather unexpected
parallelsbetweenDrosophilaandhumanorgansystemshereandhighlycon-
servedcellularmechanismsthatcontrolexosomeformationandsecretion,a
classofsecretedvesiclesthathavebeenimplicatedintumormicroenviron-
ments as well as metastasis.
Lastly, Drosophila have also been used effectively to model metabolic dis-
orders.DaenzerandFridovich-Keildiscussdiseasesofgalactosemetabolism,
primarilyresultingfromabnormalitiesinLeloirpathwayenzymeswhichare
shared between flies and mammals. Functional similarities have also been
demonstrated: for example, similar to classic galactosemias in human, flies
carrying mutations in the orthologous gene fail to thrive in the presence
of galactose and this failure was rescued with a human transgene, demon-
stratingfunctionalconservation.Thesestudiesandothers,includingidenti-
fication of motor defects and impacts on life span that parallel phenomena
seen in patients, make flies and excellent model to study genetic, environ-
mental,andpharmaceuticalinterventionsforthisimportantclassofdisease.
GrahamandPickdiscussDrosophilamodelsofdiabetesandrelateddisorders.
They describe fly models that have been generated for both Type 1 and
Type 2 diabetes, and approaches to study metabolic disorders that are
influenced by diet and other environmental factors.
While this volume was being assembled, a similar collection of articles
was published (Perrimon, Bonini, & Dhillon, 2016). In that special issue
of DMM, Bellen and coworkers provide a “Poster” illustrating three ways
in which Drosophila research contributes to the study of human disease:
reversegenetics,forwardgeneticsandadiagnosticstrategy,orpipelinethat
utilizestheUAS/GAL4systemtoassesstherolesofcandidategenes(Ugur,
Chen,&Bellen,2016).MostofthechaptersinthisvolumeofCTDBillus-
tratetheuseoftheseapproachestotackletheunderlyingbasesofarangeof
human disease. I refer the reader to both sets of collections to learn more
aboutgeneralapproachestodiseasemodelingandtoprogressmadeonspe-
cific disease types. Overall, enormous headway has been made in recent
Preface xix
years modeling human diseases in flies. This work paves the way for the
development and refinement of additional models and future progress in
translating these findings to effective drug development and disease
intervention.
LESLIE PICK
REFERENCES
Perrimon,N.,Bonini,N.M.,&Dhillon,P.(2016).Fruitfliesonthefrontline:Thetrans-
lationalimpactofDrosophila.DiseaseModels&Mechanisms,9(3),229–231.
Ugur,B.,Chen,K.,&Bellen,H.J.(2016).Drosophilatoolsandassaysforthestudyofhuman
diseases.DiseaseModels&Mechanisms,9(3),235–244.
