Building a brain in the gut development of the enteric nervous system

ClinGenet2013:83:307–316PrintedinSingapore.Allrightsreserved©2012JohnWiley&SonsA/S.PublishedbyBlackwellPublishingLtd

CLINICALGENETICSdoi:10.1111/cge.12054

DevelopmentalBiology:FrontiersforClinicalGenetics

SectionEditors:

JacquesL.Michaud,e-mail:jacques.michaud@recherche-ste-justine.qc.ca

OlivierPourqui´e,e-mail:pourquie@igbmc.fr

Buildingabraininthegut:development

oftheentericnervoussystem

GoldsteinAM,HofstraRMW,BurnsAJ.Buildingabraininthegut:

developmentoftheentericnervoussystem.

ClinGenet2013:83:307–316.©JohnWiley&SonsA/S.Publishedby

BlackwellPublishingLtd,2012

Theentericnervoussystem(ENS),theintrinsicinnervationofthe

gastrointestinaltract,isanessentialcomponentofthegut

neuromusculatureandcontrolsmanyaspectsofgutfunction,including

coordinatedmuscularperistalsis.TheENSisentirelyderivedfromneural

crestcells(NCC)whichundergoanumberofkeyprocesses,including

extensivemigrationintoandalongthegut,proliferation,and

differentiationintoentericneuronsandglia,duringembryogenesisand

fetallife.Thesemechanismsareunderthemolecularcontrolofnumerous

signalingpathways,transcriptionfactors,neurotrophicfactorsand

extracellularmatrixcomponents.Failureintheseprocessesandconsequent

abnormalENSdevelopmentcanresultinso-calledentericneuropathies,

arguablythebestcharacterizedofwhichisthecongenitaldisorder

Hirschsprungdisease(HSCR),oraganglionicmegacolon.Thisreview

focusesonthemolecularandgeneticfactorsregulatingENSdevelopment

fromNCC,theclinicalgeneticsofHSCRanditsassociatedsyndromes,

andrecentadvancesaimedatimprovingourunderstandingandtreatment

ofentericneuropathies.

Conflictofinterest

Theauthorshavenoconflictof

interest.AMGoldsteina,RMWHofstrab

andAJBurnsb,c

aDepartmentofPediatricSurgery,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,MA,USA,bDepartmentofClinicalGenetics,ErasmusMedicalCenter,Rotterdam,TheNetherlands,andcNeuralDevelopmentandGastroenterologyUnits,UCLInstituteofChildHealth,London,UK

Keywords:entericnervoussystem–Hirschsprungdisease–entericneuropathies–neuralcrestcells–RET

Correspondingauthor:AlanJ.Burns,NeuralDevelopmentandGastroenterologyUnits,UCLInstituteofChildHealth,30GuilfordStreet,London,WC1N1EH,UK.Tel.:+442079052721;fax:+442078314366;e-mail:alan.burns@ucl.ac.uk

Received2October2012,revisedandacceptedforpublication1November2012

Afunctionalgastrointestinal(GI)tractisessential

fortransporting,absorbing,digesting,andexcreting

foodandwaste,forprotectingthehostfromingested

pathogens,allergens,andtoxins,andforcontinuously

monitoringandrespondingtothestateoftheintestinal

lumen.Theprincipalconductorofthishighlyorches-

tratedsymphonyistheentericnervoussystem(ENS),

avastandcomplexnetworkofneuronsandglialcells

thatislocatedalongthelengthoftheGItractandrepre-

sentsanimportantcomponentoftheautonomicnervous

system(1).Whileextrinsicinnervationfromthecen-

tralnervoussystemcanmodulateENSfunction,the

ENSservesasanintrinsicnervoussystemforthegut,capableofcontrollingmostofthefunctionsoftheintes-

tineindependently.Itisbecauseofitscomplexityand

autonomousfunctionthattheENSisoftenreferredto

asthe‘secondbrain’(2).

TheENScontainsapproximately100millionneu-

rons(3)withinatleast18functionalclasses(4).Itis

organizedintwoconcentricringsofinterconnectedgan-

glia,consistingofbothentericneuronsandenteroglial

cells,interconnectedbyinterganglionicfibers(Fig.1).

Theouterringisthemyenteric(Auerbach’s)plexus,

locatedbetweenthecircularandlongitudinalmuscle

layers,andtheinnerringisthesubmucosal(Meiss-

ner’s)plexus,whichisabsentintheesophagus.The

307Goldsteinetal.

(a)(b)

(c)

Fig.1.Schematicshowingformationofentericnervoussystem(ENS)fromneuralcrest-derivedprecursors.(a)Vagalneuralcrest-derivedcellsentertheproximal(oral)endoftheembryonicgutandmigratealongitsentirelengthgivingrisetothemajorityoftheneuronsandgliaoftheENS.Sacralneuralcrest-derivedcellsenterthehindgutandmigrateinanoraldirectiontoformneuronsandgliainthedistalportionofthegut.(b)Inthepost-natalgut,theENSisorganizedinweb-likeplexusesthatarelocatedbetweenthemusclelayers:themyentericplexusissituatedbetweenthelongitudinalandcircularmusclelayers,andthesubmucosalplexusbetweenthecircularmuscleandthemucosa.(c)Theentericplexusescontainsmallgroupingsofentericneuronsandglia.FG,foregut;MD,midgut;HD,hindgut.

ENScontainsmanydifferenttypesofneurons,includ-

ingprimaryafferentneuronsthatsensechemicalor

mechanicalstimuliinthelumenandthensignalvia

ascendinganddescendinginterneuronstoexcitatory

andinhibitorymotoneuronsthatcontroleffectorcell

function(4).Thereflexcircuitsproducedbythese

synapticallyinterconnectedneuronsareresponsiblefor

coordinatingthemajorfunctionsoftheENS,including

theregulationofintestinalmotility,absorption,secre-

tion,andbloodflow.

Congenitalandacquiredentericneuropathiescan

leadtoserioushealthconsequences,typicallymani-

festingwithabnormalgutmotorfunction(5,6).For

example,inflammatoryentericneuropathies,whichcan

becausedbyparaneoplastic,infectious,orimmune-

mediateddiseases,canleadtogastroparesis,intestinal

pseudo-obstruction,orcolonicinertia.Deficiencies

ofselectiveneurotransmittershavebeendescribed

inesophagealachalasiaandcongenitalhypertrophic

pyloricstenosis,bothassociatedwithabnormalintesti-

nalsphincterfunction.Mitochondrialdysfunctioncan

leadtointestinaldysmotilityfromneuronalcellinjury,

asinmitochondrialneurogastrointestinalencephalopa-

thy.Entericganglioneuromas,occurringinmultiple

endocrineneoplasiatype2B,areassociatedwithsevere

colonicdysmotility(7).TheclassicentericneuropathyisHirschsprungdis-

ease(HSCR),acongenitaldiseasecharacterizedbythe

absenceofentericgangliaalongvariablelengthsofdis-

talcolon(8,9).Congenitalaganglionosis,whichoccurs

in1in5000live-births,islimitedtotherectosigmoid

colonin80%ofcases,referredtoasshort-segment

HSCR(S-HSCR),andmostcommonlypresentswith

thefailureofanewborntopassmeconiumwithin

48hoflife,oftenwithabdominaldistensionandvom-

iting.AcontrastenemaX-rayshowingnarrowingof

thedistalcolorectumwithdilationproximallysupports

thediagnosisofHSCR,andarectalbiopsyreveal-

ingtheabsenceofentericgangliamakesthedefinitive

diagnosis.Treatmentconsistsofsurgicalresectionof

theaganglionicsegmentandanastomosisofnormally

ganglionatedboweltotheanus.

Thisreviewfocusesonthemolecularandcellular

factorsregulatingENSmorphogenesis,theclinical

geneticsofHSCRanditsassociatedsyndromes,and

recentadvancesaimedatimprovingourunderstanding

andtreatmentofentericneuropathies.

DevelopmentoftheENS

TheENSisentirelyderivedfromtheneuralcrest,

atransientstructurethatarisesearlyindevelopment

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