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AGeneticOverviewofthe

Hox
Gene
byJulioFrancisco
Variationinthegenomecanleadtonewphenotypes.Suchnewlyexpressedphenotypescanbe
beneficialtoagroupoforganismsallowingthemtostriveintheirenvironment.Anexampleofsuch
evolutionaryinnovationwastheappearanceofthe
Hox
genes(alsoknownasthehomeoticgenes).The
Hox
geneswerefirstidentifiedbyBridgesinDrosophilafliesandhavebeenextensivelystudiedover
thecourseofyears(1).Itwasdeterminethatthe
Hox
genecontrolsthebodyplanofanimalsfromthe
anteroposterioraxis.Thefollowingresearchreviewwillgiveanoverviewofthe
Hox
genesincluding
theexpressionofthe
Hox
gene,andtheroleof
Hox
geneinbothstemcelldevelopmentand
regenerationprocess.Also,thispaperwilladdressthecurrentresearchesbeingconductedinsucharea.
Duetothevoluminousofresearches,thefollowingreviewwillhighlightthreemajorareas.The
followingarethethreetopicsthatwillbeaddress:
1. HoxGeneExpressioninVertebrateNervousSystem
2. Expressionof
Hox
genesinHematopoieticStemCells
3. Theroleof
Hox
geneinlimbregeneration
Overall,thisliteratureresearchwillprovideanindepthinformationofthecurrentknowledgeofthe
Hox
gene.

Hox
GeneRegulation
Hox
geneisdividedintofourgenomicclusters(
Hoxa,Hoxb,Hoxc,
and
Hoxd
)locatedonfour
differentchromosomes,consistingof13paraloggroups(2).Such
Hox
genesvariesfromspeciesto
species.Each
Hox
geneisturnONandOFFatanarrowrangeoftimeduringearlydevelopment(3).
Also,each
Hox
geneexpressionismediateddirectlybyenhancerandrepressorgeneinteractionor
throughhistonemodification.

First,
Hox
genesareregulatedbyenhancerandrepressorelements.Theseenhancerelements
arerequiredsincethe
Hox
geneislocatedconsiderablyfardistancefromthepromoterandsurrounded
bygenepoor(calleddeserts)region.Intheprocessoftranscribingthe
Hox
gene,desertgenesare
transcribed,too.Thesedesertgenesareessentialfortheexpressionof
Hox
geneinwhichthe
completeremovalofthedesertgenewouldleadtofulllossof
Hox
expression(4).

Furthermore,therepressorturnOFFthegenebybindstothepromoterregionand,thus,
preventingthetranscriptionfromoccurring(5).However,thereisnotonlyonesetof
Hox
gene
expressed.Thereareduplicationsof
Hox
genesexpressed(6).
Inadditiontothegeneticregulation,histoneprovidesanadditionallevelofcomplexitytogene
expression.Expressionof
Hox
geneismediatedbythemethylationofhistone.Forexample,Malloand
Alonso(2013)studiedthemethylationoftwocertain
Hox
gene,H3k27m3andH3k4m3.Thesegene
wereanalyzedattipofamouseembryotail.The
Hox
geneexpressionwasfollowedthedisappearance
ofH3k27m3byatrimethylationatLys27ofhistoneH3andappearanceofH3k4m3byatrimethylation
atLys4ofhistoneH3.Suchresearchdemonstratedthemethylatedpathwayof
Hox
geneexpression.
Also,thepositioninwhichthe
Hox
geneislocatedplaysavitalroleinexpressionspecificities.
Inotherwords,justhavingthe
Hox
geneinthegenomeisnotenoughtocauseparticularspecialization.
Thegenehastobelocatedatparticularlocustocausespecialization.

HoxGeneExpressioninVertebrateNervousSystem
Despitethefactthat
Hox
genesareprominentregulatoryofbodymorphology,current
researchesarelookingintohowthe
Hox
genesareexpressedinthenervoussystemofvertebrates.This
sectionwilldiscussthe
Hox
genefunctionalrolesinthenervoussystem.
First,thebrainandcentralnervoussystem(CNS)ishighlyorderedanddiverse.Suchorderly
formationofthebrainandCNSisgovernedbygeneticactivities.The
Hox
geneisoneofmanygenes
thatplayavitalroleinarrangingandpatterningtheCNSduringdevelopment.Itwasreportedthatthe

Hox
geneisinvolvedmainlyinspecifyingtherhombomeresterritory(e.g.thehindbrainandspinal
cord)oftheCNS.(3)
Also,studiesshowedthatthe
Hox
geneplaysaparticularroleinneuronaldifferentiationand
identificationbydirectingtheaxonstoreachtheirtargetsinresponsetoenvironmentalcues.Ifthere
wasamisexpressionofthe
Hox
gene,thiscouldresultintheaxontomaneuverintotheincorrect
location.Forexample,themisexpressionofchickHoxc6inthemesodermresultedintheoutgrowthof
thespinalnerveaxons.Thiswasduetothelackofinstructivemesodermalsignals(3).Overall,the
Hox
geneisnecessaryforproperdevelopmentofthenervoussystem.

ExpressionofHoxgenesinStemCells
Stemcellscanundergoselfrenewalanddifferentiationintoprogenitorcells.Therearemany
areasintheresearchofhowthe
Hox
genesaffectsstemcells.Duetotheoverflowofinformation,the
followingreviewwillfocustheeffectofthe
Hox
geneonthehematopoieticstemcells.

HoxGenesinHematopoieticStemCellsDevelopment
Bloodcellsareclassifiedintotwomaingroups:lymphoidcells(lymphocytes,lymphoblasts,
andplasmacells)andmyeloidcells(granulocytesandmonocytesFig.2).Thesebloodcellspossess
shortlifespanandmustbeconstantlyselfrenewed.Allbloodisderivedandselfrenewedfrom
pluripotentcellscalledhematopoieticstemcells(HSCs3).Thedifferentiationandproliferationof
HSCismediatedbyanorganismsgene.
Geneticmanipulationthroughamplificationordeprivationofthe
Hox
geneinHSChas
providedvaluabledataontheeffectof
Hox
genedifferentiationandproliferation.Forexample,
overexpressionof
Hoxa10
,
Hoxb3
,and
Hoxb6
inmouseBMcellshadprofoundeffectssuchas
inhibitingthedifferentiationofBandTcell,impairingerythropoiesis,andinducing
myeloproliferativedisorderandleukemia.Also,datashowedthat
Hoxb4
deficientmouseexhibit
reductioninHSC.Studiesshowedthattheroleofthe
Hoxb4
geneistostimulateHSCexpansion.Such

expansionpromotesymmetricalselfrenewal.However,
Hoxb4
genewasnottheonly
Hox
genethat
promotedexpansion,other
Hox
genes(e.g.
Hoxb3
)hasthisexpansionability(2)

Fromhttp://cnx.org/contents/966c32cc3d6f4f4eaf4fea0c975e825c@4/
Cellular_Differentiation
Figure2.
Anoverviewoftheproductionofmaturebloodcellsbytheproliferationanddifferentiation
ofhematopoieticstemcells.

Hox
geneandlimbregenerationinUrodeles
Urodeles(i.e.salamandersandnewt)hasbeenthemodelanimalinthestudyoflimb
regeneration.Urodelesregenerationabilityisnotlimitedtoonlythelimbsandappendages.Many
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organscanreformincludingthelens,retina,intestine,cardiacventricle,upperandlowerjaws,and
tail(8).Tounderstandthefunctionof
Hox
genesinregenerationoflimbs,afoundationalknowledge
ofthecellularmechanismofthelimbregenerationinurodelesmustberecognized.
Therearethreestageinthereformationofalimb(Fig.2).Thefirststagebeginsafterthelimb
ofanurodeleisamputated.Thewoundhealingprocessbegins.Withinthefirsthourthebasal
epitheliumcellsattheedgeofthewoundstarttomigrateacrosstheamputatedsection.Thisprocessof
coveringthewoundingsitewithepitheliumcellisknownasepithelialization.Ittypicallytakes24
hourstocovertheentireamputatedsitewithepitheliumcells.Thenewlyformedepitheliumcells
beginstothickenwithinfewdaysduetoepidermiscellscalledkeratinocytesthatmigrateand
proliferate,formingawoundepithelium.Leukocytessuchasmacrophagebegintoaccumulateatthe
injuredsite(8).Next,maturecellsunderneaththeformedepitheliumbeginstodedifferentiateinorder
toproliferateintoblastema.Inthesecondstage,theblastemabeginsexpansionandgrowth.Inthethird
stage,thecellstarttodifferentiateandgrowintoanewlydevelopedlimb(9).

From

http://www.nature.com/jid/journal/v131/n12/fig_tab/jid2011223f6.html#figuretitle

Figure2.Ageneraloverviewoflimbregenerationinurodeles.
Therearethreestageofdevelopment
inurodeles.Inthefirststage,thewoundiscoveredupwithwoundepithelium,andthematuretissue
undertheepitheliumbeginstodedifferentiate.Theseundifferentiatedandproliferatingcellsform
blastema.Inthenextstage,theblastemaexpandsandstartstogrow.Inthelaststage,thecells
differentiateandreformsthemissinglimbs(16).
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Researchersdemonstratedtheimportantroleof
Hox
geneinwoundhealingandthe
dedifferentiationprocess.Forexample,Christen,Beck,Lombardo,andSlack(2003)studiedthe
expressionofthree
AbdominalB
type
Hox
gene(XHoxc10,XHoxa13,andXHoxd13)in
Xenopus
.The
researchersdemonstratedthatthese
Hox
genesareexpressedduringdifferenttemporalandspatial
settings.ItwasreportedthatXHoxc10isupregulatedatthesiteofdedifferentiatedand
undifferentiatedcellarerecruited.XHoxa13,ontheotherhand,isexpressionduringtheproliferationof
theblastemalcells.Overall,theexpressionofthe
Hox
geneiscrucialfortheregenerationofanew
limb.

ConcludingRemark
Hox
geneplaysacriticalroleinthemanybiologicalprocess.Infact,thelossofthe
Hox
gene
canleadtomajordeficits.Forexample,thedisruptionofHoxa3resultinthelossofthethymus.Also,
thelossoftheHoxa1/Hoxd11,andHoxc11canresultinthelossoffunctionofthemetanephrickidney
(10).
Todescribethecompleteroleofthe
Hox
geneisbeyondthelimitofthisreport,buttheoverall
functionistodeterminetheanteriorandposteriorbodyplanofanorganism.

LITERATURECITED
1. GehringW.J.2007.Thehomeoboxasakeyforunderstandingtheprinciplesofthegenetic
controlofdevelopment.In
HOXGeneExpression
,113.SpringerNewYork
2. ArgiropoulosB&HumphriesRK.2007.Hoxgenesinhematopoiesisandleukemogenesis.
Oncogene
.26:67666776
3. EstacioGmezA,DazBenjumeaF,J.2014.Rolesofhoxgenesinthepatterningofthecentral
nervoussystemofdrosophila.
Fly
.8:2632.
4. SoshnikovaN.2014.Hoxgenesregulationinvertebrates.DevelopmentalDynamics.243:
4958.JacobF,PerrinD,SanchezC,MonodJ.1960.Operon:agroupofgeneswiththe
expressioncoordinatedbyanoperator.C.R.Hebd.SeancesAcad.Sci.250:172729.
5. Duboule,D.2007.TheriseandfalloftheHoxgeneclusters.Development134:254960.
6. GunsiliusE,GastlG,PetzerAL.2001.Hematopoieticstemcells.Biomedicine&
Pharmacotherapy.55:18694
7. Mescher,A.L.1996.Thecellularbasisoflimbregenerationinurodeles.Int.J.Dev.Biol.4:
785795.
8. ChristenB,BeckCW,LombardoA,SlackJMW.2003.Regenerationspecificexpression
patternofthreeposteriorhoxgenes.DevelopmentalDynamics.226:34955
9. GoutiM,GavlasA.2007.Hoxgenesamdstemcells.InHOXGeneExpression,ed.Spyros
Papageorgiou,111129.NewYork,NY:Springer.
10. MalloM,AlonsoCR.2013.Theregulationofhoxgeneexpressionduringanimaldevelopment.
Development.140:395163.