Thebroadgoalofthisworkistounderstandhowembryoscoordinatethefusionand separationofepithelialsheetsduringearlydevelopment.Aprimaryexampleofthisoccurs duringneuraltubeclosurewhenthelateraledgesoftheneuralprimordium(theneural folds)meetatthemidlineandfusetoseparateaclosedneuraltubefromacontinuous overlyingepidermis.Thisprocessisknownaszipperingbecauseitproceedsdirectionally frominitialpointsalongtheanterior-?posterioraxisfrominitialpointsofcontact.Zippering iscommontomanyformsofepithelialfusion,buthowitworksispoorlyunderstood.Akey challengeistounderstandhowtheforcesareproducedthatpulltheneuralfoldstogether anddrivethezipperforwardandhowtheseforcesarecontrolledinspaceandtimeto achievea WewilladdressthesechallengesusingtheinvertebratechordateCionaintestinalisasa modelsystem.Cionaoffersauniquelytractableopportunitytostudyaverysimpleformof epithelialzipperingandneuraltubeclosureinvolvingveryfewcellswithwell-?developed toolsformoleculargeneticmanipulation,transgenesisandhigh-?speedliveimaging.In recentwork,weshowedthatzipperingispoweredbyadynamicsequenceofactomyosin-? dependentjunctioncontractionsthatsweepsfromposteriortoanterioralongthelateral edgesoftheneuralplate.Wewilluseahighlyinterdisciplinarycombinationofquantitative imaging,experimentalmanipulationsandpredictivemodelingtoaskthefollowing questions: (1) Howisthiswaveofcontractioncontrolledthroughcell-?cellsignalingalongthe Neural/Epidermalboundaryandbetweenneuralfoldsacrossthemidline? (2) Whatarethesignalingpathwaysthatmediatethiscontrol? (3) Howarelocalsignaling,forceproductionandtissueremodelingintegratedto createaself-?propagatingwaveofjunctioncontractionandtissuefusionacross theembryo? Becausemanyofthemoleculesthatmediatecell-?cellsignalingandforceproductionare highlyconservedacrossthemetazoa,ourworkwillhavedirectrelevancetounderstanding neuraltubeclosureandtissuefusiongenerallyinhigherchordates,anditwillprovidenew insightsintohowfailuresinthisprocesscanleadtobirthdefectsinhumans.
The work proposed here aims to elucidate fundamental mechanisms that govern spatiotemporal patterning of forces that drive neural tube closure, using the invertebrate chordate Ciona intestinalis as a model system. Failures in neural tube closure are a leading cause of birth defects in humans. Much of the machinery that underlies force production in embryonic cells, and that signals between cells to pattern those forces, are highly conserved. Therefore, the results of this work should have make direct contributions to understanding neural tube closure in higher vertebrates, and how failures in this process lead to birth defects in humans.
| Lang, Charles F; Munro, Edwin (2017) The PAR proteins: from molecular circuits to dynamic self-stabilizing cell polarity. Development 144:3405-3416 |
