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Towards a Cellular and Molecular Understanding of Neurulation

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Towards a Cellular and Molecular Understanding of Neurulation DEVELOPMENTALDYNAMICS221:117–145(2001) REVIEWS APEERREVIEWEDFORUM TowardsaCellularandMolecularUnderstandingof Neurulation JEAN-FRANC¸OISCOLASANDGARYC.SCHOENWOLF* DepartmentofNeurobiologyandAnatomy,UniversityofUtahSchoolofMedicine,SaltLakeCity,Utah ABSTRACT Neurulationoccursduring causeneurulationdefects,therebycontribut- theearlyembryogenesisofchordates,andit ingtotheformationofneuraltubedefects. resultsintheformationoftheneuraltube,a ©2001Wiley-Liss,Inc. dorsalhollownervecordthatconstitutesthe rudimentoftheentireadultcentralnervous Keywords:biophysicaldeterminantsofform; system.Thegoalofstudiesonneurulationisto canalizationofdevelopment;cell understanditstissue,cellularandmolecular behaviors;centralnervoussystem; basis,aswellashowneurulationisperturbed chickembryo;folicacid;genes;he- duringtheformationofneuraltubedefects. redity;mouseknockouts;morpho- Thetissuebasisofneurulationconsistsofa genesis;neuralfolds;neuralgroove; seriesofcoordinatedmorphogeneticmove- neuralplate;neuraltubedefects mentswithintheprimitivestreak(e.g.,regres- (NTDs);neurulationdefects sionofHensen’snode)andnascentprimary germlayersformedduringgastrulation.Sig- INTRODUCTION nalingoccursbetweenHensen’snodeandthe Neurulationiscommonlydescribedasthedevelop- nascentectoderm,initiatingneurulationbyin- mentalprocessthatresultsintherollingupofaflat ducingtheneuralplate(i.e.,actually,bysup- sheetofepithelialcellsintoanelongatedtube.Buthow pressingdevelopmentoftheepidermalecto- doesneurulationactuallyoccur?Doesneurulation derm).Tissuemovementssubsequentlyresult merelyinvolvethereadoutofanevolvedgeneticpro- inshapingandbendingoftheneuralplateand gram,orareothergoverning(i.e.,epigenetic)princi- closureoftheneuralgroove.Thecellularbasis plesinvolved?Aretherekeyneurulationgenesthat ofthetissuemovementsofneurulationconsists haveevolvedspecificallytoregulatethisprocess?What ofchangesinthebehavioroftheconstituent exactperturbationsinneurulationresultintheforma- cells;namely,changesincellnumber,position, tionofneuraltubedefects? shape,sizeandadhesion.Neurulation,likeany Inthisarticle,wewilladdressthesequestionsby morphogeneticevent,occurswithinthemilieu reviewingthetissueandcellularbasisofneurulation ofgenericbiophysicaldeterminantsofform andprovidingstrategiesfordeterminingitsmolecular presentinalllivingtissues.Suchforcesgovern basis.Identifyingthecauseofmorphogenesiswillre- andtosomedegreecontrolmorphogenesisina quireafullunderstandingoftheinteractionbetween tissue-autonomousmanner.Themolecularba- genericbiophysicaldeterminantsofformpresentinall sisofneurulationremainslargelyunknown, livingtissues(e.g.,viscoelasticcharacteristics,surface butwesuggestthatneurulationgeneshave tensions)andgenesthatregulatemorphogenesis(e.g., evolvedtoworkinconcertwithsuchdetermi- bycontrollingitstimingandthedirectionandmagni- nants,sothatappropriatechangesoccurinthe tudeofthecellbehaviorsthatdrivemorphogenetic behaviorsofthecorrectpopulationsofcellsat movements)(Weiss,1950;NewmanandComper,1990; thecorrecttime,maximizingtheefficiencyof DrasdoandForgacs,2000;Hogeweg,2000).Wecon- neurulationandleadingtoheritablespecies- siderherethepotentialrolesofsuchgenericbiophysi- andaxial-differencesinthisprocess.Inthis article,wereviewthetissueandcellularbasis ofneurulationandprovidestrategiestodeter- Grantsponsor:theNationalInstitutesofHealth;Grantnumber: NS18112. mineitsmolecularbasis.Weexpectthatsuch *Correspondenceto:GaryC.Schoenwolf,Ph.D.,Departmentof strategieswillleadtotheidentificationinthe NeurobiologyandAnatomy,UniversityofUtahSchoolofMedicine,50 nearfutureofcriticalneurulationgenes,genes N.MedicalDrive,SaltLakeCity,Utah84132. E-mail:[email protected] thatwhenmutatedperturbneurulationina Received29December2000;Accepted22February2001 highlyspecificandpredictablefashionand Publishedonline2May2001 ©2001WILEY-LISS,INC. 118 COLAS AND SCHOENWOLF Fig. 1. Whole-mounts of chick embryos undergoing primary neurula- approximate borders are outlined. D, The paired neural folds have come tion, viewed from the dorsal surface of the blastoderm. The range of into contact at the level of the future mesencephalon region of the neural stages shown (Hamburger and Hamilton, 1951, stages 4–11) represent tube (arrow). E, A neural tube has formed throughout the length of the about 24 hours of development (i.e., one day out of 21 in the life of a chick future brain and much of the length of the future spinal cord. hn, Hensen’s embryo), beginning at about 18 hours of incubation and ending at about node; n, notochord (seen through the neural plate); nf, neural fold; ng, 42 hours of incubation. A, The neural plate has just formed; its approx- neural groove; np, neural plate; nt/b, future brain level of the neural tube; imate borders are outlined. B, The neural plate is undergoing shaping; its nt/sc, future spinal cord level of the neural tube; ps, primitive streak. approximate borders are outlined. C, The neural plate is initiating bend- Modified from Smith and Schoenwolf (1997). ing, establishing a neural groove, while still undergoing shaping; its cal determinants of form in neurulation, to define bet- The details of neural induction are beyond the scope of ter the influence of putative neurulation genes on the this review (reviewed by Lemaire and Kodjabachian, characteristic morphology of the resulting neural tube. 1996; Tanabe and Jessell, 1996; Gould and Grainger, We focus our discussion principally on the avian model, 1997; Hemmati-Brivanlou and Melton, 1997; Sasai and because this system has been the one most studied Robertis, 1997; Weinstein and Hemmati-Brivanlou, mechanistically. Additionally, we provide a classifica- 1999; Harland, 2000; Jessell and Sanes, 2000). How- tion scheme for identifying neurulation genes, and we ever to summarize, recent studies have shown that use this scheme to classify those genes that have al- neural induction actually involves suppression of an ready been mutated in mouse embryos, leading to the epidermal fate rather than induction of a neural fate, formation of neural tube defects (NTDs), either specif- so that the default state of the naive ectoderm is neu- ically by directly altering critical events of neurulation, ral, not epidermal as suggested by classical studies. or more generally, by adversely affecting early embry- The suppressive signal is generated by Hensen’s node onic growth and morphogenesis. (Fig. 1A), the avian equivalent of Spemann’s organizer, THE TISSUE BASIS OF NEURULATION: and it involves the binding of inhibitory molecules to COORDINATED MORPHOGENETIC secreted ligands, such as BMPs or Wnts, blocking their MOVEMENTS signaling. At the tissue level, neurulation occurs in four stages: Formation of the Neural Plate formation of the neural plate, shaping of the neural plate, bending of the neural plate and closure of the Aside from the issue of neural induction, formation neural groove (Fig 1). The stages of neurulation are of the neural plate involves apicobasal thickening of coordinated with movements of the primitive streak; the ectoderm, resulting in the formation of a placode, namely, progression (i.e., rostrocaudal elongation) of a flat but thickened epithelial rudiment. The neural the primitive streak during formation of the neural plate can form in isolation from the surrounding plate, and regression of the primitive streak (and espe- epidermal ectoderm (Schoenwolf, 1988), demonstrat- cially of its rostral end, Hensen’s node) during shaping ing that once the ectoderm becomes committed to a and bending of the neural plate and closure of the neural fate, the process of formation of the neural neural groove. Neurulation begins with the formation plate is autonomous to the prospective neural plate of the neural plate, a process that is typically described and does not required the presence of non-neural as induction of the neural plate or neural induction. ectodermal cells. NEURULATION GENES 119 Shaping of the Neural Plate tion, convergence occurs principally at future brain At the time of its formation, the neural plate when levels (i.e., levels at which dorsolateral hinge points viewed dorsally or ventrally is shaped like a spade form). shield, being relatively wide mediolaterally and short Tissue isolation experiments demonstrate that bend- rostrocaudally (Fig. 1A). The caudal “wings” of the ing of the neural plate is driven by changes in both spade shield flank Hensen’s node, the inducer of the neuroepithelial cells (driving furrowing) and the adja- neural plate. During shaping of the neural plate, the cent cells of the epidermal ectoderm (driving folding). nascent neural plate continues to thicken apicobasally. Thus, in the prospective median hinge point, furrowing Additionally, it undergoes a convergent extension of the neural plate occurs when this region is separated movement; that is, it concomitantly narrows mediolat- from more lateral tissues, but elevation of the neural erally (i.e., transversely) and elongates rostrocaudally folds requires the presence of such lateral non-neuro- (Fig. 1B, C). epithelial tissues (Schoenwolf, 1988; Moury and Schoenwolf, 1995). Moreover, although furrowing is Tissue isolation experiments demonstrate that shap- driven in the median hinge point by changes in the ing of the neural plate is driven by changes in the cells forming this structure, such furrowing requires an behavior of its neuroepithelial cells; thus, the neural inductive signal from the underlying notochord (Smith plate still undergoes shaping when it is separated from and Schoenwolf, 1989). This signal, mediated by the more lateral tissues (i.e., epidermal
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