Polarization of migrating cortical neurons by Rap1 and N-cadherin: Revisiting the model for the Reelin signaling pathway.

2011·1.4 MB·English

by  Jossin, Yves

EXTRAVIEW
SmallGTPases2:6,322–328;November/December2011;G2011LandesBioscience
Polarization of migrating cortical neurons by Rap1 and N-cadherin
Revisiting the model for the Reelin signaling pathway
Yves Jossin
DivisionofBasicSciences;FredHutchinsonCancerResearchCenter;Seattle,WAUSA;InstituteofNeuroscience;UniversityofLouvainMedicalSchool;Brussels,Belgium
Neuronal migration is essential for nucleotide Exchange Factors (GEFs) that
the development of the cerebral induce GTP loading and inhibited by
cortex. Mutations leading to defective GTPase Activating Proteins (GAPs) that
migration are associated with numerous return them into their GDP loaded
brain pathologies. An important challenge inactive form.1 The large superfamily of
© 2012 Lain thenfielddis to uenderstsand t heBintrinsiic osmallsGTPcases(ialsoenamendtheRcassueper- .
and extrinsic mechanisms that regulate family) is comprised of the Ras/Rap/Ral,
neuronal migration during normal deve- Rho, Rab, Arf and Ran families.2 They
lopment and in disease. Many small regulate a wide variety of essential cellular
GTPases are expressed in the central processes such as cell division, adhesion,
nervoussystemduringembryonicdevelop- polarity, migration and differentiation.3 It
ment. Recent findings have shown that is thus not surprising that many of their
Do not distribute.
Rap1anditsdownstreampartnersRal,Rac membersareinvolveddirectlyorindirectly
andCdc42areinvolvedinthemaintenance innumerouspathologicalconditionsinclud-
of N-Cadherin at the plasma membrane ingcancerandbraindevelopmentaldiseases.
whichisnecessaryforthecorrectpolariza- This extra view will focus on the Rap
tion of migrating neurons. The activation subfamily of small GTPases. It is com-
of Rap1 is triggered by Reelin, an extra- posedoffiverelatedproteins,Rap1(Aand
cellular protein known for its role in the B) and Rap2 (A, B and C) which have
organization of the cortex into layers of overlapping functions and patterns of
neurons.IntheabsenceofReelin,neurons expression. Rap1 in particular has been
exhibit a broader and irregular pattern of intensively studied for its role in the
positioning.Theprevailingmodelsuggests regulation of integrin-mediated cell adhe-
that Reelin signals to neurons during the sion and the control of endothelial and
laststepoftheirmigration,anotionthatis epithelial cadherin-based cell-cell junction
inconsistent with new data describing an integrity.4 We have recently demonstrated
Keywords: Rap, polarity, neuronal effectofReelinonearlystepsofmigration. a new function of Rap1 in regulating the
migration, cadherin, Reelin, reeler, cortex, InregardtotheserecentfindingsIsuggest polarity of migrating neurons in the
brain, mouse a revised model, which I call the “polarity developing mouse brain cortex through
model,” that further refines our under- the control of N-Cadherin (NCad).5 We
Submitted: 08/31/11
standing of the developmental function found that Reelin, an extracellular matrix
Revised: 09/27/11
playedbyReelinanditsdownstreamsmall protein which has an important function
Accepted: 10/03/11 GTPases. in the organization of the cortex, triggers
the activation of Rap1 in cortical neurons
http://dx.doi.org/10.4161/sgtp.2.6.18283
when they are midway through their
Correspondenceto:YvesJossin;
Introduction migration path, at a stage where re-
Email:[email protected]
polarization occurs. These new findings
Small GTPases are guanine nucleotide donotfitwiththecurrentmodelinwhich
ExtraViewto:JossinY,CooperJA.Reelin,Rap1
andN-cadherinorientthemigrationofmul- binding proteins that function as mole- Reelin affects neurons at the end of their
tipolarneuronsinthedevelopingneocortex.Nat cular switches by cycling between active migration.Here,Isuggestarevisedmodel
Neurosci2011;14:697–703;PMID:21516100; GTP-bound and inactive GDP-bound of action for the Reelin signaling pathway
http://dx.doi.org/10.1038/nn.2816
states. They are activated by Guanine withacentralfunctionforsmallGTPases.
322 SmallGTPases Volume2Issue6
Iwillstartthisextraviewwithadescrip- migration starting with a polarized migra- Similar toallsmallGTPases,Rap proteins
tion of the development of the cerebral tion within the VZ. This is followed by a are regulated by specific GAPs or GEFs.
cortex and the recently discovered role more complex movement within the mul- Important clues for their involvement in
played by Rap1. Then I will discuss the tipolarmorphologyzone(MMZ),which is brain development came from the pheno-
downstream proteins involved in this func- madeupofthe sub-ventricular zone (sVZ) type of a hypomorphic mutant mouse for
tion,followedbytheupstreamReelinsignal. andthelowerpartoftheintermediatezone C3G, a Rap-specific GEF, which exhibits
(IZ),wheretheyundergomoredivisions.6,7 an accumulation of neurons within the
Cortical Development and Rap1 Importantly, at this stage, the neurons lose MMZ.8 This arrest in cell migration is
Small GTPases their bipolar morphology and elongate mainly due to the highly disorganized
several neurites which is why they have radial glia fibers (the main migration
Thedevelopmentofthebrainrequiresthat been referred as having a multipolar substrate for this type of cell) and
neuronsmigrateawayfromtheirbirthplace morphology. This occurs along with a disintegration ofthebasement membrane.
inordertoperformtheirfunctionsproperly. slowermigrationandafewswitchesintheir Moreover, these mice die around E14.5
Inaddition,neuronshavetoextendneurites direction of movement. The neurons then making it difficult to study the migration
and ultimately differentiate and commun- migrate within theradialmorphology zone oflaterbornneurons.C3Gisnottheonly
icate with each other. Characterization of (RMZ),comprisingtheupperpartoftheIZ GEF regulating Rap during the develop-
the molecular signaling pathways involved andthecorticalplate(CP),toreachthetop ment of the cortex. In fact, a dorsal
incerebralcortexdevelopmentisimportant of the CP. During the transition from telencephalon-specific knockout of PDZ-
for the understanding of brain pathologies MMZtoRMZ,theychangemorphologyto GEF-1, another activating protein for
©such as l2issence0phaly, 1microc2ephaly, pLeri- abecomnebipodlaronceeagains.Wit hinBtheCPi, oRap1sandcRap2ienezymens, resuclts inethe .
ventricular heterotopia, epilepsy, dyslexia, new neurons migrate past the older ones accumulation of neurons underneath a
mental retardation, schizophrenia, bipolar already installed resulting in “inside-out normally developed cortex.9 The involve-
disorder, and many others resulting from layering,” that is, a gradient of cells with mentofRapactivatorsincorticaldevelop-
defective cortical architecture, connectivity younger neurons in the outermost field of ment suggested that Rap enzymes might
and function. The majority of neurons in theCPandolderneuronsmoreinside. also play an important role. Indeed, the
the cortex are the excitatory glutamatergic During the multipolar stage, and in neuron-specific inhibition of Rap (i.e.,
Do not distribute.
neurons that are generated from progeni- spite of the multiple changes of direction without affecting radial glial cells) in vivo
tor cells located at the ventricular zone of migration, the net movement is still induces an ectopic accumulation of
(VZ) which lines the ventricle (Fig.1). directedtowardtheCP.Rap1hasemerged neurons within the MMZ.5 Time lapse
These neurons undergo different phases of as a critical regulator of this polarization.5 video-microscopy revealed that this
Figure1.Migrationofglutamatergicneuronsinthemammaliancerebralcortex.Neuronsarebornintheventricularzone(VZ)fromprogenitorcells
(greencells).TheystartmigrationasbipolarcellsthenmigrateasmultipolarcellswhentheymoveintotheMultipolarMorphologyZone(MMZ),which
containsthesub-ventricularzone(sVZ)andthelowerpartoftheintermediatezone(IZ).NeuronsresumeabipolarmigrationwhentheyentertheRadial
MorphologyZone(RMZ)comprisingtheupperpartoftheIZandthecorticalplate(CP).WithintheCP,neuronsmigratepasttheothercellsalready
installedandsettlejustbeneaththemarginalzone(MZ)resultinginformationofaninside-outlayeredstructure:TheCPisdividedintolayersIItoVI,with
layerIIconsistingofyoungerlater-borncellsandlayerVIconsistingoftheoldestcells.Cx,cortex;V,ventricle;arrowsshowdirectionofmigration.
www.landesbioscience.com SmallGTPases 323
phenotype is not the result of defective integrity and segregation of different cell Andfinally,overexpressionofNCadinthe
neuronal motility of the affected multi- populations. Indeed, throughout develop- cortex is able to partially rescue the cell
polar cells, but is rather due to a defect in ment, NCad is highly expressed in the positioning defect due to inhibition of
their polarization toward the RMZ. This vertebrate central nervous system and its Rap1. These data suggest that Rap1
is because the movement of the Rap- conditional deletion in the dorsal telence- activity is important in migrating neurons
inhibited neurons is randomized with a phalon results in disruption of the adhe- in order to maintain the high level of
decreased net movement toward the rensjunctionslocalizedattheapicalendof NCad at the plasma membrane necessary
RMZ. This phenotype is not due to a neuroepithelial cells, where NCad is most to allow cells to polarize correctly. Yet
complete arrest of invasion of the RMZ highly concentrated. This results in a we do not know whether other cadherins,
because many cells migrate out of the generaldisruptionofneuroepithelialinteg- also expressed at the MMZ, might have
MMZ,albeitwithasignificantdelaywhen rity and aberrant radial glia fibers that do some redundant function with NCad. In
compared with control cells. Surprisingly, not expand toward the pial surface.12 addition, how NCad allows the polariza-
the subsequent radial bipolar migration However, evidence is emerging that cad- tion of cortical neurons is still under
along glial fibers (also called glia-guided herinsalsoregulatecellularmotility.Inthe investigation. Nevertheless, hypotheses
locomotion)isnotaffectedbytheabsence rat caudal hindbrain, classic cadherins might be suggested. NCad may be
of Rap activity. This absence of effect on regulate tangential migration of precere- activated locally in order to increase the
locomotion has been confirmed in an in bellar neurons.13 In the zebrafish, NCad binding to radially-oriented processes on
vitro lattice culture system where disso- concentrates transiently at the front of otherneuronsorglialfibers.Thisadhesion
ciated neurons move along glial fibers. cerebellar granule cells during the initia- could stabilize the position of the centro-
©Toget her,2these0observ1ations2sugges t tLhat ation nof thdeir cheain-msigratio nBand iis osomes. A sicmilarimoedel hans beencsuggeested .
Rapisimportantfortheinitialpolarization required for them to polarize prior to for the directional chain migration of
of neurons but not migration per se. migrate.14 In the early chick embryo cerebellar granule neurons in the zebrafish
PDGFsignalingcontrolsNCadexpression with NCad transiently accumulating at
Rap1 Polarizes Neurons Through in mesoderm cells, which is required for the front of the cells.14 However, in other
Its Regulation of N-Cadherin, with efficient migration.15 Interestingly, C3G cell types, it is the cadherin-free cell edge
a Potential Involvement of Ral, and PDZ-GEF1, two of the Rap-specific that shows the polarity of migration.
Do not distribute.
Rac and Cdc42 GEFs known to be important for mam- Indeed, cadherin-mediated cell-cell inter-
malian brain development (see above), actions induce the centrosome and Golgi
Signaling through the small GTPase Rap1 have also been linked to the cadherins. apparatus to move toward the free cell
has been implicated in both integrin- In epithelial cells, C3G directly interacts edgesinculturedastrocytes19andstimulate
mediated and cadherin-mediated adhesion with E-cadherin and is important for the protrusions at the free edge in Xenopus
events.Todate,studiesexaminingneuron- initial steps of adherens junction forma- neural crest cells.20 Alternatively, NCad
specific deletion of β1 Integrins10 or the tion,16,17 while PDZ-GEF1 is recruited may be a regulator for other cell surface
Integrin downstream effector FAK (focal by MAGI-1 at VE-cadherin-mediated receptors that respond to directional
adhesion kinase)11 did not observe any endothelial cell-cell adhesions.18 signals from the CP. For example, NCad
defect in glia-guided migration. On the Our recent findings demonstrated that modulates FGF-2 signaling in MCF-7
other hand, both Rap1 and cadherins and in the mammalian cerebral cortex NCad breast cancer cells21 and VE-cadherin
theirinteractionareemergingasimportant has an important function in polarizing regulates TGFβ signaling in endothelial
regulators during the brain development. cortical neurons before they are able to cells.22 This model has parallels with the
Classical cadherins are single-pass trans- start migrating into the RMZ.5 The migration of Drosophila border cells,
membrane adhesion receptors involved in inhibition of cadherins in post-mitotic where Drosophila ECad (DECad) is
cell-cell contact and epithelial polarity neurons without affecting progenitor cells required in the migrating cells as well as
through calcium dependent homophilic andtheirradialgliafibers,recapitulatesthe in the cells they migrate between.23 The
binding. Intracellularly, cadherins interact phenotype induced by inhibition of Rap1 border cells extend a long leading process,
withcateninfamilymembers.p120-catenin i.e., loss of polarity during the multipolar whose direction is specified by a growth
binds to the juxtamembrane region of migration with no effect on the speed of factor gradient but whose formation
cadherin to stabilize it at the plasma mem- migration as multipolar or bipolar neu- requires DECad.24 The induction of the
brane, while a- and β-catenin serve a dyn- rons. Several experiments confirmed that long extensions on border cells may be
amic role in linking cadherin to the actin NCad functions downstream from Rap1. analogous to the induction of a radial
cytoskeleton.Manymembersofthecadherin First, inhibition of Rap1 in vivo and in leading process on cortical neurons, and
family are expressed in the central nervous vitro reducedthepresence ofNCadatthe in both cases surface cadherin expression
systemandoneofthem,NCad,hasrecently plasma membrane with a concomitant may be key to developing the polarity
attractedtheinterestofneuroscientists. increase in intracellular NCad. Second, a needed for migration.
The prevailing view is that cadherin functional assay demonstrated that inhibi- According to studies in epithelial and
functions to mediate adhesion between tion of Rap1 reduced the binding of endothelialcells,Rapusesseveralmechan-
stationary cells, thereby maintaining tissue neuronstotheNCadextracellulardomain. isms to regulate cadherin traffic (Fig.2).
324 SmallGTPases Volume2Issue6
The Rap effector RalGDS activates RalA, with the actin cytoskeleton.31 Finally, might facilitate the directional vesicle
which docks secretory vesicles to the activation of Rac1 and Cdc42 by Rap1 transport of E-cadherin and/or organize
exocyst complex and recycles E-Cadherin could also stabilize cadherins at the the actin cytoskeleton, enabling neighbor-
to epithelial cell-cell junctions.25 It has membrane through their target IQGAP1. ing cells to contact one another. Other
been shown that Rap1, Rac1 and Cdc42, Studies have suggested two possibilities regulatory pathways have also been pro-
activated by nectins, are able to trigger as to how they work. First, it has been posed such as the interaction of Rap1
the formation of adherens junctions in proposed that IQGAP1 destabilizes cad- with AF6, increasing AF6 association
epithelial cells and fibroblasts.26,27 This herins by inducing their dissociation withp120cateninwhichinturnstrength-
positionsthemupstreamofcadherinfunc- from a-catenin and IQGAP1 is negatively ens the interaction of p120 catenin with
tion. However, they also can be activated regulatedbyRac1andCdc42.31,32Second, E-cadherin, reducing its internalization
downstream of cadherins,17,28 suggesting a another study suggested that IQGAP and/or degradation.34
potential positive feedback loop. In epi- stabilizes cadherins through the reorgani- Although migrating neurons are differ-
thelial cells, Rap1 is important for the zation of the actin cytoskeleton and is ent from static epithelial cells making
recruitment of E-cadherin into nascent positively regulated by Rac1 and Cdc42.33 contacts, Rap1, Ral, Rac and Cdc42 may
cell-cell contact sites16,29 and in this Regardless of which of these pathways function similarly to regulate cell to cell
process it functions upstream of Rac1 downstream of Rap1 are predominant, contact of cortical neurons through the
and Cdc42 by recruiting their GEF perhaps depending on cell types or regulation of NCad.5 Our inhibition and
Vav2.16,17 Cdc42 has been reported to experimental conditions, all those results rescue experiments in the animal and in
regulate the trafficking of basolateral indicate that, in epithelial cells, stimu- vitro suggested that Ral, Rac and Cdc42
©memb ran2e prote0ins30 a1s well2as to m odLu- alationnof Radp1 maey indusce th e aBctivatioin omaysalso cplay airoele infnluencincg Reap1’s .
late the association of cell-cell contacts of Ral, Rac and/or Cdc42, which in turn effect on the presence of NCad at the
plasma membrane and the resulting func-
tion on polarity of cortical neurons.5 This
process is likely to be very dynamic and
control of the amount of cadherins at the
cell surface must be tightly regulated by a
Do not distribute.
balancebetweenendocytosisandrecycling
to the sites of new contact formation. Of
note, a recent study demonstrated the
involvementofRab5-dependentendocytic
and Rab11-dependent recycling pathways
in the regulation of NCad in cortical
neurons,35 while, in epithelial cells,
Rap1 has been shown to co-localize with
E-cadherinattheRab11-positiverecycling
endosome compartment.36 It would be of
interest to determine whether Rap1 and
the Rab pathways work in parallel or
cooperatively in the regulation of NCad
and neuronal migration. Another import-
ant next step would also be to investigate
whether the exocyst, downstream of Ral,
orIQGAPandotherproteinsdownstream
of Rac and Cdc42, play roles in the
polarization of cortical neurons through
the Rap1/NCad pathway.
Figure2.RegulationofcadherinsbyRap1andotherdownstreamsmallGTPases.Rap1induces Reelin Polarizes Multipolar
adherensjunctionformationbystabilizingcadherinsattheplasmamembrane.Maintenanceof
NeuronsToward the RMZ Through
cadherinsatjunctionscantaketheformofincreasedexocytosis,decreasedendocytosis,increased
Rap1 and NCad: A New Model
recyclingattheplasmamembraneorremodelingoftheactincytoskeletonunderneaththe
junctions.Thosefunctionscanbeaccomplishedbytheactivationofdifferentpathways of Action
downstreamofRap1suchassignalsinvolvingthesmallGTPasesRal,Rac,Cdc42orRab11.Rap1
alsoinhibitsthetargetingofcadherinsfordegradationthroughanAF6/p120-cateninpathway. An important question is what stimulates
ActivationofRap1dependsonspecificGEFssuchasPDZ-GEForC3Gthatarerecruitedbycadherin
Rap1 and its downstream effectors in the
clusteringorbyothersignals.
polarization of migrating neurons.
www.landesbioscience.com SmallGTPases 325
Reelin is an extracellular protein This model explains why, in the absence than just an inversion of laminar fate.39
secreted by Cajal-Retzius cells present in of Reelin, the inside-out layering of the This suggests that the current model may
the marginal zone above the RMZ and is cortex is inverted. However, it is impor- not fully explain the phenotype. Earlier
requiredforthecorrectorganizationofthe tant to point out that the reeler cortical studies already indicated that Reelin may
CP.37 The prevailing model suggests that phenotype is not simply an inversion of signal the neurons before they start their
Reelin acts on migrating neurons when the neuronal layering. Even though the radial migration within the RMZ. First,
they arrive at the top of the RMZ during earliest neurons shift from a deep laminar the active cleavage fragment of Reelin has
their final somal translocation (named position to form a superficially located been shown to diffuse from the marginal
“detach and go” because cells would superplate in the reeler brains, the later zoneintothedeeptissue.40Second,cellsin
detach from the radial glia then proceed born neurons exhibit a broader and the MMZ express the highest level of
through the final somal translocation).38 irregular distribution which is far more functionalReelinreceptors.41Recently,we
Figure3.Regulationofneuronalmigration
withinthemammaliancerebralcortexbythe
Reelin/Rap1/N-cadherinpathwayandothersmall
GTPases.(A)ReelinsignalsthroughRap1(andits
downstreamenzymesRal,RacandCdc42)and
N-cadherinonneuronsattheMMZtopolarize
themtowardtheRMZ.Rab5andRab11might
alsobeinvolved.Thesubsequentglia-guided
© 2012 Landes Bioscience.
migrationwithintheRMZisindependentof
Reelin,Rap1orN-cadherin.Duringthismigration,
theReelinsignalisdownregulated(degradation
ofphosphorylatedDab1,downregulationof
functionalreceptors)andN-cadherinisdown-
regulatedbytheRab7pathwaywhichmaybea
consequenceofthedownregulationoftheReelin
Do not distribpatuhway.Wtheneneuro.nsreachthetopofthe
RMZ,theyundergoafinalsomaltranslocation.
Thisfinalsomaltranslocationcoulddependon
thereductionoftheReelinsignalor,alternatively,
Reelinmayinduceasecondsetofintracellular
signalsincellsperformingthefinalsomal
translocationastheyaremorematurethanwhen
theyencounteredReelinforthefirsttimeinthe
RMZandareinadifferentbiologicalcontext.(B)
IntheabsenceofReelin,Rap1orN-cadherin,
neuronsaredisorientedwithintheMMZ.Rab5or
Rab11inhibitioninducesasimilarphenotype.In
theabsenceofReelinorRab7,thefinalsomal
translocationisalsoaffectedandcouldbe,at
leastinpart,aconsequenceofdefective
N-cadherindownregulation.
326 SmallGTPases Volume2Issue6
showed that inhibition of Reelin by in Dab1 which is consequently degraded.45,46 they reach the top of the RMZ. It is then
uteroelectroporationdelaysthecellsatthe It is therefore likely that membrane- plausible that Reelin triggers two different
MMZandaffectsthelocalizationofNCad associated NCad levels are downregulated intracellular signals in the immature
at their plasma membrane, mimicking because the Reelinsignal is not any longer multipolarandinthemorematurebipolar
the phenotype caused by Rap inhibition. there to maintain it at the membrane. neurons as they are predicted to express
Rescue experiments in vivo confirmed Indeed, NCad also exhibits a downregula- different sets of intracellular signaling
that Rap1 is involved in this phenotype tion of its expression in the wild-type molecules and are surrounded by different
downstream of Reelin. These data suggest RMZ, which is much less pronounced in cues and/or extracellular matrix proteins.
that Reelin is, at least in part, responsible the reeler brain.5 Interestingly, the down- In this case, the “polarity model” is not
for the Rap1/N-cadherin-mediated polar- regulation of theReelin signal seems to be mutually exclusivewith, but complement-
ization function in neurons migrating an important event for a correct neuronal arytotheprevious“detachandgo”model
within the MMZ. In agreement with this, positioning.45,46 A testable prediction because they affect migrating neurons at
NCad protein levels are decreased in the would be that the downregulation of two different steps of their journey.
embryonic reeler mutant cerebral cortex NCad depends on the decreased Reelin
exclusively at the MMZ.5 A function of signal. Indeed, a recent study showed that Future Directions
Reelin through Rap1 and NCad on Rab7-dependent degradation of NCad is
polarity of neurons before they enter the also important for the final phase of The next challenge in the field is to
RMZ may better explain the disorganized migration when neurons reach the top of determine exactly how Rap1 and its client
positioning of late-born neurons. Indeed, the RMZ.35 Therefore, I propose a model GTPases RalA/B, Rac and Cdc42 affect
©in th e a2bsence0of a1polar2izing s ignLal, a(Fig.3n) in wdhich eReelinsfirst trigBgers thie othe spolaritcy oficoertical nneuroncs. Oether .
neurons would exit the MMZ in a polarization of neurons when they are at small GTPases such as members of the
disorderly manner disregarding their date the MMZ by activating Rap1 and stabi- Rab family might also come into play.
of birth. It is surprising that Reelin affects lizing NCad at the plasma membrane but, How all those small GTPases finely tune
the polarization of neurons because pre- and at the same time as phosphorylated neuronal migration needs to be investi-
vious experiments showed that the local- Dab1 and the Reelin signal are down- gated in more details. How NCad, and
ization of the source of Reelin is not regulated, NCad is also degraded through maybe other cadherins, regulate the polar-
Do not distribute.
important for its function in the CP.42,43 a Rab7 pathway when neurons migrate ized movement of cortical neurons is also
The polarization mediated by Reelin may as bipolar cells. This downregulation at ground for future work. Reelin certainly
thusbeindirect.Reelinwouldratheractas the end of their migration might be as doesnotworkaloneanditwillbeexciting
a permissive signal allowing neurons to important as the upregulation at the to uncover the interconnection of the
respondtoanothercuewhichstillremains multipolar stage. In this view, the final multiple signals that regulate the develop-
to be discovered. somaltranslocationisaconsequenceofthe ment of the cerebral cortex.
After neurons have received the polar- downregulation of the Reelin signal that
izing cue triggered by Reelin, the signal is was initiated when the cells were in the Acknowledgments
downregulated.Previousworkshaveshown MMZ. I gratefully thank J.A. Cooper, R.N.
that neurons downregulate the signal and/ In the above model, Reelin signals only Eisenman, S.M. Parkhurst and V.
or become less responsive to Reelin once inmultipolarcells.However,itisalsocon- Vasioukhin, for helpful comments on the
they commence migration within the ceivable that Reelin stimulates migrating manuscript. Y.J.issupportedbytheFonds
RMZ. For example, Reelin induces the neurons twice: first at the MMZ and a National de la Recherche Scientifique
downregulation of its functional receptors second hit later during the final somal (Belgium) and the European Commission,
at the time neurons migrate within the translocation.Neuronsmightberefractory 7th framework program, under the Marie
RMZ.41,44 Also, Reelin induces the phos- to Reelin signaling after the first stimu- Curie International Outgoing Fellowship
phorylation of the intracellular adaptor lation but become sensitive again when Program.
References 4. Boettner B, Van Aelst L. Control of cell adhesion 7. ShoukimasGM,HindsJW.Thedevelopmentofthe
dynamics by Rap1 signaling. Curr Opin Cell Biol cerebral cortex in the embryonic mouse: an electron
1. BosJL,RehmannH,WittinghoferA.GEFsandGAPs:
2009;21:684-93;PMID:19615876;http://dx.doi.org/ microscopic serial section analysis. J Comp Neurol
criticalelementsinthecontrolofsmallGproteins.Cell
10.1016/j.ceb.2009.06.004 1978;179:795-830;PMID:641236;http://dx.doi.org/
2007; 129:865-77; PMID:17540168; http://dx.doi.
5. JossinY,CooperJA.Reelin,Rap1andN-cadherinorient 10.1002/cne.901790407
org/10.1016/j.cell.2007.05.018
themigrationofmultipolarneuronsinthedeveloping 8. VossAK,BrittoJM,DixonMP,SheikhBN,CollinC,
2. Wennerberg K, Rossman KL, Der CJ. The Ras
neocortex. Nat Neurosci 2011; 14:697-703; PMID: TanSS,etal.C3Gregulatescorticalneuronmigration,
superfamily at a glance. J Cell Sci 2005; 118:843-6;
21516100;http://dx.doi.org/10.1038/nn.2816 preplate splitting and radial glial cell attachment.
PMID:15731001;http://dx.doi.org/10.1242/jcs.01660
6. NoctorSC,Martinez-CerdenoV,IvicL,KriegsteinAR. Development 2008; 135:2139-49; PMID:18506028;
3. FrischeEW,ZwartkruisFJ.Rap1,amercenaryamong Cortical neurons arise in symmetric and asymmetric http://dx.doi.org/10.1242/dev.016725
the Ras-like GTPases. Dev Biol 2010; 340:1-9;
divisionzonesandmigratethroughspecificphases.Nat
PMID:20060392; http://dx.doi.org/10.1016/j.ydbio.
Neurosci2004;7:136-44;PMID:14703572;http://dx.
2009.12.043
doi.org/10.1038/nn1172
www.landesbioscience.com SmallGTPases 327
9. BilasySE,SatohT,UedaS,WeiP,KanemuraH,AibaA, 22. Rudini N, Felici A, Giampietro C, Lampugnani M, 35. Kawauchi T, Sekine K, Shikanai M, Chihama K,
etal.Dorsaltelencephalon-specificRA-GEF-1knockout CoradaM,SwirsdingK,etal.VE-cadherinisacritical Tomita K, Kubo K, et al. Rab GTPases-dependent
micedevelopheterotopiccorticalmassandcommissural endothelialregulatorofTGF-betasignalling.EMBOJ endocytic pathways regulate neuronal migration and
fiber defect. Eur J Neurosci 2009; 29:1994-2008; 2008; 27:993-1004; PMID:18337748; http://dx.doi. maturation through N-cadherin trafficking. Neuron
PMID:19453629; http://dx.doi.org/10.1111/j.1460- org/10.1038/emboj.2008.46 2010; 67:588-602; PMID:20797536; http://dx.doi.
9568.2009.06754.x 23. NiewiadomskaP,GodtD,TepassU.DE-Cadherinis org/10.1016/j.neuron.2010.07.007
10. BelvindrahR,Graus-PortaD,GoebbelsS,NaveKA, required for intercellular motility during Drosophila 36. BalzacF,AvolioM,DeganiS,KaverinaI,TortiM,
Muller U. Beta1 integrins in radial glia but not in oogenesis. J Cell Biol 1999; 144:533-47; PMID: SilengoL,etal.E-cadherin endocytosisregulates the
migratingneuronsareessentialfortheformationofcell 9971747;http://dx.doi.org/10.1083/jcb.144.3.533 activityofRap1:atrafficlightGTPaseatthecrossroads
layers in the cerebral cortex. J Neurosci 2007; 24. FulgaTA,RorthP.Invasivecellmigrationisinitiated between cadherin and integrin function. J Cell Sci
27:13854-65; PMID:18077697; http://dx.doi.org/10. byguidedgrowthoflongcellularextensions.NatCell 2005; 118:4765-83; PMID:16219685; http://dx.doi.
1523/JNEUROSCI.4494-07.2007 Biol 2002; 4:715-9; PMID:12198500; http://dx.doi. org/10.1242/jcs.02584
11. Beggs HE, Schahin-Reed D, Zang K, Goebbels S, org/10.1038/ncb848 37. Jossin Y. Neuronal migration and the role of reelin
Nave KA, Gorski J, et al. FAK deficiency in cells 25. GrindstaffKK,YeamanC,AnandasabapathyN,HsuSC, duringearlydevelopmentofthecerebralcortex.Mol
contributing to the basal lamina results in cortical Rodriguez-BoulanE,SchellerRH,etal.Sec6/8complex Neurobiol2004;30:225-51;PMID:15655250;http://
abnormalities resembling congenital muscular dystro- is recruited to cell-cell contacts and specifies transport dx.doi.org/10.1385/MN:30:3:225
phies. Neuron 2003; 40:501-14; PMID:14642275; vesicledeliverytothebasal-lateralmembraneinepithelial 38. CooperJA.Amechanismforinside-outlaminationin
http://dx.doi.org/10.1016/S0896-6273(03)00666-4 cells.Cell1998;93:731-40;PMID:9630218;http://dx. the neocortex. Trends Neurosci 2008; 31:113-9;
12. Kadowaki M, Nakamura S, Machon O, Krauss S, doi.org/10.1016/S0092-8674(00)81435-X PMID:18255163; http://dx.doi.org/10.1016/j.tins.
RadiceGL,TakeichiM.N-cadherinmediatescortical 26. OgitaH,TakaiY.ActivationofRap1,Cdc42,andrac 2007.12.003
organization in the mouse brain. Dev Biol 2007; by nectin adhesion system. Methods Enzymol 2006; 39. BoyleMP,BernardA,ThompsonCL,NgL,BoeA,
304:22-33; PMID:17222817; http://dx.doi.org/10. 406:415-24; PMID:16472674; http://dx.doi.org/10. Mortrud M, et al. Cell-type-specific consequences of
1016/j.ydbio.2006.12.014 1016/S0076-6879(06)06030-7 reelindeficiencyinthemouseneocortex,hippocampus,
13. TaniguchiH,KawauchiD,NishidaK,MurakamiF. 27. Fukuyama T, Ogita H, Kawakatsu T, Fukuhara T, and amygdala. J Comp Neurol 2011; 519:2061-89;
Classic cadherins regulate tangential migration of YamadaT,SatoT,etal.Involvementofthec-Src-Crk- PMID:21491433;http://dx.doi.org/10.1002/cne.22655
precerebellar neurons in the caudal hindbrain. C3G-Rap1 signaling in thenectin-induced activation 40. JossinY,GuiL,GoffinetAM.ProcessingofReelinby
Development 2006; 133:1923-31; PMID:16611692; ofCdc42andformationofadherensjunctions.JBiol embryonicneuronsisimportantforfunctionintissue
© 2012 Landes Bioscience.
http://dx.doi.org/10.1242/dev.02354 Chem2005;280:815-25;PMID:15504743 but not in dissociated cultured neurons. J Neurosci
14. RiegerS,SenghaasN,WalchA,KosterRW.Cadherin-2 28. KraemerA,GoodwinM,VermaS,YapAS,AliRG. 2007; 27:4243-52; PMID:17442808; http://dx.doi.
controlsdirectionalchainmigrationofcerebellargranule Racisadominantregulatorofcadherin-directedactin org/10.1523/JNEUROSCI.0023-07.2007
neurons. PLoS Biol 2009; 7:e1000240; PMID: assembly that is activated by adhesive ligation inde- 41. UchidaT,BabaA,Perez-MartinezFJ,HibiT,MiyataT,
19901980; http://dx.doi.org/10.1371/journal.pbio. pendentlyofTiam1.AmJPhysiolCellPhysiol2007; LuqueJM,etal.DownregulationoffunctionalReelin
1000240 292:C1061-9;PMID:17020937;http://dx.doi.org/10. receptors in projection neurons implies that primary
15. Yang X, Chrisman H, Weijer CJ. PDGF signalling 1152/ajpcell.00073.2006 Reelin action occurs at early/premigratory stages. J
controlsthemigrationofmesodermcellsduringchick 29. PriceLS,Hajdo-MilasinovicA,ZhaoJ,ZwartkruisFJ, Neurosci 2009; 29:10653-62; PMID:19710317;
gastrulation by regulatiDng N-cadoherin ex prenssion. oCotllard JG,dBos JLi. Rsap1 regtulatesrE-caidherbin- uhttp:/t/dx.doei.org/10..1523/JNEUROSCI.0345-09.2009
Development 2008; 135:3521-30; PMID:18832396; mediated cell-cell adhesion. J Biol Chem 2004; 42. JossinY,IgnatovaN,HiesbergerT,HerzJ,Lambertde
http://dx.doi.org/10.1242/dev.023416 279:35127-32; PMID:15166221; http://dx.doi.org/ Rouvroit C, Goffinet AM. The central fragment of
16. Hogan C, Serpente N, Cogram P, Hosking CR, 10.1074/jbc.M404917200 Reelin, generated by proteolytic processing in vivo, is
Bialucha CU, Feller SM, et al. Rap1 regulates the 30. Kroschewski R, Hall A, Mellman I. Cdc42 controls criticaltoitsfunctionduringcorticalplatedevelopment.J
formation of E-cadherin-based cell-cell contacts. Mol secretory and endocytic transport to the basolateral Neurosci2004;24:514-21;PMID:14724251;http://dx.
CellBiol2004;24:6690-700;PMID:15254236;http:// plasmamembraneofMDCKcells.NatCellBiol1999; doi.org/10.1523/JNEUROSCI.3408-03.2004
dx.doi.org/10.1128/MCB.24.15.6690-6700.2004 1:8-13;PMID:10559857 43. MagdalenoS,KeshvaraL,CurranT.Rescueofataxia
17. FukuyamaT,OgitaH,KawakatsuT,InagakiM,TakaiY. 31. FukataM,KurodaS,NakagawaM,KawajiriA,ItohN, andpreplatesplittingbyectopicexpressionofReelin
ActivationofRacbycadherinthroughthec-Src-Rap1- ShojiI,etal.Cdc42andRac1regulatetheinteractionof in reeler mice. Neuron 2002; 33:573-86; PMID:
phosphatidylinositol 3-kinase-Vav2 pathway. Oncogene IQGAP1 with beta-catenin. J Biol Chem 1999; 11856531;http://dx.doi.org/10.1016/S0896-6273(02)
2006;25:8-19;PMID:16170364 274:26044-50; PMID:10473551;http://dx.doi.org/10. 00582-2
18. SakuraiA,FukuharaS,YamagishiA,SakoK,KamiokaY, 1074/jbc.274.37.26044 44. Morimura T, Hattori M, Ogawa M, Mikoshiba K.
MasudaM,etal.MAGI-1isrequiredforRap1activation 32. KurodaS,FukataM,NakagawaM,FujiiK,Nakamura Disabled1regulatestheintracellulartraffickingofreelin
uponcell-cellcontactandforenhancementofvascular T,OokuboT,etal.RoleofIQGAP1,atargetofthe receptors. J Biol Chem 2005; 280:16901-8; PMID:
endothelial cadherin-mediated cell adhesion. Mol Biol small GTPases Cdc42 and Rac1, in regulation of 15718228;http://dx.doi.org/10.1074/jbc.M409048200
Cell2006;17:966-76;PMID:16339077;http://dx.doi. E-cadherin-mediatedcell-celladhesion.Science1998; 45. Bock HH, Jossin Y, May P, Bergner O, Herz J.
org/10.1091/mbc.E05-07-0647 281:832-5; PMID:9694656; http://dx.doi.org/10. Apolipoprotein E receptors are required for reelin-
19. DupinI,CamandE,Etienne-MannevilleS.Classical 1126/science.281.5378.832 induced proteasomal degradation of the neuronal
cadherinscontrolnucleusandcentrosomepositionand 33. IzumiG,SakisakaT,BabaT,TanakaS,MorimotoK, adaptor protein Disabled-1. J Biol Chem 2004;
cell polarity. J Cell Biol 2009; 185:779-86; PMID: TakaiY.EndocytosisofE-cadherinregulatedbyRac 279:33471-9; PMID:15175346; http://dx.doi.org/10.
19487453;http://dx.doi.org/10.1083/jcb.200812034 and Cdc42 small G proteins through IQGAP1 and 1074/jbc.M401770200
20. Theveneau E, Marchant L, Kuriyama S, Gull M, actinfilaments.JCellBiol2004;166:237-48;PMID: 46. SimóS,JossinY,CooperJA.Cullin5regulatescortical
Moepps B, Parsons M, et al. Collective chemotaxis 15263019;http://dx.doi.org/10.1083/jcb.200401078 layering by modulating the speed and duration of
requires contact-dependent cell polarity. Dev Cell 34. HoshinoT,SakisakaT,BabaT,YamadaT,KimuraT, Dab1-dependentneuronalmigration.JNeurosci2010;
2010; 19:39-53; PMID:20643349; http://dx.doi.org/ Takai Y. Regulation of E-cadherin endocytosis by 30:5668-76; PMID:20410119; http://dx.doi.org/10.
10.1016/j.devcel.2010.06.012 nectin through afadin, Rap1, and p120ctn. J Biol 1523/JNEUROSCI.0035-10.2010
21. Suyama K, Shapiro I, Guttman M, Hazan RB. A Chem 2005; 280:24095-103; PMID:15857834;
signalingpathwayleadingtometastasisiscontrolledby http://dx.doi.org/10.1074/jbc.M414447200
N-cadherinandtheFGFreceptor.CancerCell2002;
2:301-14; PMID:12398894; http://dx.doi.org/10.
1016/S1535-6108(02)00150-2
328 SmallGTPases Volume2Issue6