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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD088831-04
Application #
9702071
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Henken, Deborah B
Project Start
2016-07-18
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Lang, Charles F; Munro, Edwin (2017) The PAR proteins: from molecular circuits to dynamic self-stabilizing cell polarity. Development 144:3405-3416