23 an introduction to genetic analysis.docx

23 an introduction to genetic analysis.docx

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23anintroductiontogeneticanalysis

Chapter23

DevelopmentalGenetics

KeyConcepts

Aprogrammedsetofinstructionsinthegenomeofahigherorganismestablishesthedevelopmentalfatesofcellswithrespecttothemajorfeaturesofthebasicbodyplan.

Developmentalpathwaysareformedbythesequentialimplementationofvariousregulatorysteps.

Thezygoteistotipotent,givingrisetoeveryadultcelltype;asdevelopmentproceeds,successivedecisionsrestricteachcelllineagetoitsparticularfate.

Gradientsofmaternallyderivedregulatoryproteinsestablishpolarityalongthemajorbodyaxesoftheegg;theseproteinscontrolthelocaltranscriptionalactivationofgenesencodingmasterregulatoryproteinsinthezygote.

Manyproteinsthatactasmasterregulatorsofearlydevelopmentaretranscriptionfactors;othersarecomponentsofpathwaysthatmediatesignalingbetweencells.

Somefatedecisionsaremadeautonomouslybyindividualcells;manyfatedecisionsrequirecommunicationandcollaborationbetweencells.

ThesamebasicsetofgenesidentifiedinDrosophilaandtheregulatoryproteinsthattheyencodeareconservedinmammalsandappeartogovernmajordevelopmentaleventsinmany—perhapsall—higheranimals.

Introduction

Inallhigherorganisms,lifebeginswithasinglecell,thenewlyfertilizedegg.Itreachesmaturitywiththousands,millions,oreventrillionsofcellscombinedintoacomplexorganismwithmanyintegratedorgansystems.Thegoalofdevelopmentalbiologyistounravelthefascinatingandmysteriousprocessesthatachievethetransfigurationofeggintoadult.Becauseweknowmoreaboutdevelopmentintheseorganisms,wewillrestrictmostofourdiscussiontoanimalsystems.

Thedifferentcelltypesofthebodyaredistinguishedbythevarietyandamountsoftheproteinsthattheyexpress—theproteinprofileofeachcell（thatis,thequantitativeandqualitativearrayofproteinsthatitcontains）.Theproteinprofileofacellinamulticellularorganismistheendresultofaseriesofgeneticregulatorydecisionsthatdeterminethe“when,where,andhowmuch”ofgeneexpression.Thus,foraparticulargene,weareinterestedinwhichtissuesandatwhatdevelopmentaltimesthegeneistranscribedandhowmuchofthegeneproductissynthesized.Fromageneticist'spointofview,alldevelopmentalprogrammingthatcontrolsanorganism'sproteinprofilesisdeterminedbytheregulatoryinformationencodedintheDNA.Wecanlookatthegenomeasapartslistofallthegeneproducts（RNAsandpolypeptides）thatcanbepotentiallyproducedandasaninstructionmanualofwhen,where,andhowmuchoftheseproductsaretobeexpressed.Thus,oneaspectofdevelopmentalgeneticsistounderstandhowthisinstructionmanualoperatestosendcellsdowndifferentdevelopmentalpathways,ultimatelyproducingalargeconstellationofcharacteristiccelltypes.

Thisaspectisnotallthatwewanttounderstandaboutdevelopmentalgeneticsandproductionofcellulardiversity,however.Wealsowanttounderstandhowthesedifferentcelltypesaredeployedinacoherentandconstructivedistribution—inotherwords,howtheybecomeorganizedintoorgansandtissuesandhowthoseorgansystemsandtissuesareorganizedintoanintegrated,coherentlyfunctioningindividualorganism.

Centralthemesofdevelopmentalgenetics

Thegeneralbodyplaniscommontoallmembersofaspeciesand,indeed,iscommontomanyverydifferentspecies.Allmammalianspecieshavefourlimbs,whereasallinsectshavesix.Butallmammalsandinsectsmust,inthecourseoftheirdevelopment,differentiatetheanteriorfromtheposteriorendandthedorsalfromtheventralside.Eyesandlegsalwaysappearintheappropriateplaces.Exceptforseveredisturbancesthatinterferewithdevelopment,thebasicbodyplanofaspeciesappearstobequiteimmunefromenvironmentalmodification.Thestudyofthebasicdevelopmentofbodyplancanthenbecarriedoutbystudyingtheinternalgeneticprogramoftheorganismwithoutreferencetotheenvironment.Weshouldnotforget,however,thatthestudyofthegeneticdeterminationofthesebasicdevelopmentalprocessesdoesnotprovideuswithanexplanationofthephenotypicdifferencesbetweenindividualmembersofaspecies.Thischapterfocusesontheprocessesunderlyingpatternformation,theconstructionofcomplexform,andhowtheseprocessesoperatereliablytoexecutethedevelopmentalprogramforthebasicbodyplan.

Logicofbuildingthebodyplan

Duringtheelaborationofthebodyplan,cellscommittospecificcellfates;thatis,thecapacitytodifferentiateintoparticularkindsofcells.Thecellfatecommitmentshavetomakesenseinregardtothelocationofthecell,becauseallorgansandtissuesaremadeupofmanycellsandtheentirestructureofanorganortissuerequiresacooperativedivisionoflaboramongtheparticipatingcells.Thus,somehow,cellpositionmustbeidentified,andfateassignmentsmustbeparceledoutamongacooperatinggroupofcells—calledadevelopmentalfield.

Positionalinformationisgenerallyestablishedthroughproteinsignalsthatemanatefromalocalizedsourcewithinacell（theinitialone-cellzygote）orwithinadevelopmentalfield.Itisthemolecularequivalenttoestablishingtherulesforgeographiclongitudesandlatitudes.Justasweneedlongitudesandlatitudestonavigateontheearth,cellsneedpositionalinformationtodeterminetheirlocationwithinadevelopmentalfieldandtorespondbyexecutingtheappropriatedevelopmentalprogram.Whenthatpositionalinformationhasbeencaptured,generallyafewintermediatecelltypesarecreatedwithinafield.Throughfurtherprocessesofcelldivisionanddecisionmaking,apopulationofcellswiththenecessaryfinaldiversityoffateswillbeestablished.

Thesefurtherprocesses—faterefinement—canbeoftwotypes.Insomesituations,throughasymmetricdivisionsofoneoftheintermediatetypesofcells,descendantsarecreatedthathavereceiveddifferentregulatoryinstructionsandthereforebecomecommittedtodifferentfates.Thiscanbethoughtofasacelllineage-dependentmechanismforpartitioningfates.Inothersituations,suchfatedecisionsaremadebycommittee—thatis,thefateofacellbecomesdependentoninputfromneighboringcellsandfeedbacktothemthroughparacrinesignalingmechanisms（seeChapter22）.Suchneighborhood-dependentdecisionsareextremelyimportant,becausethechemicaldialogbetweencellsensuresthatallfateshavebeenallocatedandthatthepatternofallocationiscoherent.Thecellneighborhood-dependentmechanismsalsoprovideforacertaindevelopmentalflexibility.Developmentalmechanismsneedtobeflexiblesothatanorganismcancompensateforaccidentssuchasthedeathofsomecell.Ifsomecellsarelostthroughaccidentalcelldeath,thenormalparacrineintercellularcommunicationisthenabortedandthesurvivingneighborscanbecomereprogrammedtodivideandinstructasubsetoftheirdescendantstoadoptthefatesofthedeceasedcells.Indeed,theregenerationofseveredlimbs,asoccursinsomeanimals,isamanifestationofthepowerofspecificationversushard-wireddeterminationinbuildingpattern.

MESSAGE

Cellswithinadevelopmentalfieldmustbeabletoidentifytheirgeographiclocationsandmakedevelopmentaldecisionsinthecontextofthedecisionsbeingmadebytheirneighbors.

Theconsequenceoftheprecedingscenariofordevelopmentisthattheprocessofcommitmenttoaparticularfateisagradualone.Acelldoesnotgoinonestepfrombeingtotallyuncommitted,ortotipotent,tobecomingearmarkedforasinglefate.Eachmajorpatterningdecisionis,inactuality,aseriesofeventsinwhichmultiplecellsthatareatthesameleveloffatecommitmentare,instep-by-stepfashion,assigneddifferentfates.Astheseeventsunfold,cellproliferationisgenerallyoccurring.Thus,ifweexamineacelllineage—thatis,afamilytreeforasomaticcellanditsdescendants—weseethatparentalcellsinthetreearelesscommittedthantheirdescendants.

MESSAGE

Ascellsproliferateinthedevelopingorganism,decisionsaremadetospecifymoreandmorepreciselythefateoptionsofcellsofagivenlineage.

Majordecisionsinbuildingtheembryo

Avarietyofdevelopmentaldecisionsareundertakenintheearlyembryotogivecellstheirproperidentitiesandtobuildthebodyplan.Someofthemaresimplebinarydecisions:

Separationofthegermline（thegamete-formingcells）fromthesoma（everythingelse）.

Establishmentofthesexoftheorganism.（Ordinarily,allcellsofthebodymakethesamechoice.）

Thesebinarydecisionstendtobemadeatonedevelopmentalstageand,asweshallseelater,areexamplesofirreversiblefatedetermination.

Theothermajordecisionsconcernmultiplefateoptionsandfarmoreintricatedecision-makingpathways;theyleadtothecomplexpatternelementsofthebodyplan,composedalmostentirelyofthesomaticcells.Mostofthemarespecificationdecisionstakenbylocalpopulationsofcells:

Establishmentofthepositionalinformationnecessarytoorientandorganizethetwomajorbodyaxesoftheembryo:

anterior–posterior（fromheadtotail）anddorsal–ventral（frombacktofront）.

Subdivisionoftheembryonicanterior–posterioraxisintoaseriesofdistinctunitscalledsegmentsormetameresandassignmentofdistinctrolestoeachsegmentaccordingtoitslocationinthedevelopinganimal.

Subdivisionoftheembryonicdorsal–ventralaxisintotheouter,middle,andinnersheetsofcells,calledthegermlayers,andassignmentofdistinctrolestoeachoftheselayers.

Productionofthevariousorgans,tissues,systems,andappendagesofthebody