review article the dynamic of the apical ectoplasmic...

Review ArticleThe Dynamic of the Apical Ectoplasmic Specialization betweenSpermatids and Sertoli Cells The Case of the Small GTPase Rap1

Giovanna Berruti and Chiara Paiardi

Department of Biosciences University of Milan 20133 Milano Italy

Correspondence should be addressed to Giovanna Berruti giovannaberrutiunimiit

Received 12 December 2013 Accepted 19 January 2014 Published 27 February 2014

Academic Editor Nicola Bernabo

Copyright copy 2014 G Berruti and C Paiardi This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Despite advances in assisted reproductive technologies infertility remains a consistent health problem worldwide Spermiationis the process through which mature spermatids detach from the supporting Sertoli cells and are released into the tubule lumenSpermiation failure leads to lack of mature spermatozoa and if not occasional could result into azoospermia major cause ofmale infertility in human population Spermatids are led through their differentiation into spermatozoa by the apical ectoplasmicspecialization (aES) a testis-specific actin-based anchoring junction restricted to the Sertoli-spermatid interface The aES helpsspermatid movement across the seminiferous epithelium promotes spermatid positioning and prevents the release of immaturespermatozoa To accomplish its functions aES needs to undergo tightly and timely regulated restructuring Even if components ofaES are partly known the mechanisms through which aES is regulated remains still elusive In this review we propose a model bywhich the small GTPase Rap1 could regulate aES assemblyremodellingThe characterization of key players in the dynamic of aESsuch as Rap1 could open new possibility to develop prognostic diagnostic and therapeutic approaches for male patients undertreatment for infertility as well as it could lead to the identification of new target for male contraception

1 Introduction

Spermatogenesis is a very complex and regulated process dur-ing which the diploid spermatogonia divide and differentiateinto haploid spermatozoa [1ndash4]

The correct development of fertile spermatozoa relieson the peculiar organization of the seminiferous epithe-lium The germinal component (spermatogonia primaryand secondary spermatocytes round spermatids and elon-gatingelongated spermatids) is strictly interconnected withthe somatic component the Sertoli cells which sustainsspermatogenesis giving structural support and nourishmentto germ cells [5 6] In mouse adult testis the germ cellsat different stages of differentiation display a unique patternof association with Sertoli cells which can be classified intotwelve stages (from I to XII) [1 2 4]

During these stages spermatids undergo massive mor-phological modifications such as acquisition of cell polaritycondensation of chromatin formation of the acrosome andtail and production and elimination of the residual body

Meanwhile the differentiation process takes place spermatidsmigrate across the entire length of the seminiferous epithe-lium until they reach the luminal edge where mature spermsare finally released [1 7] So it is clear that germ cells haveto remain anchored to Sertoli cells till the final steps in orderto avoid a premature release as immature spermatids withconsequence on the male fertility potential (Figure 1)

The integrity of seminiferous epithelium and the func-tional cell interconnections are maintained through severaljunctional devices that take place between both the Sertoli-Sertoli cells and the Sertoli-germ cells Besides junctiontypes present also in other epithelia like tight junctions [8ndash10] and gap junctions [11 12] the seminiferous epitheliumexhibits testis-unique anchoring junctions as the ectoplasmicspecialization (ES) [13 14] and the desmosome-like junction[15]

The ES between the Sertoli cells is known as basalES (bES) At the basal compartment (Figure 1) the bEScoexists with other junctional structures like tight junctiongap junction and desmosome-like junction all together

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 635979 9 pageshttpdxdoiorg1011552014635979

2 BioMed Research International

aESaES

BTB

SpermiationaES

disassembly

Round spermatid

Elongating spermatid

Elongated spermatid

Mature sperm

Sertoli cell

Sertoli cell

Pachytenespermatocyte

Basa

l com

part

men

tAd

lum

inal

com

part

men

t

Preleptotenespermatocyte

Apical ectoplasmic specialization

Basal ectoplasmic specialization

Tight junctionGap junctionDesmosome-like junction

Disassembled apical ES

Spermatogonium

Figure 1 A schematic drawing showing the junctions between Sertoli-Sertoli cells and Sertoli-germ cells as discussed in the review Thedrawing illustrates two Sertoli cells embracing germ cells at different stages of differentiation The Sertoli-Sertoli cell contacts namely tightjunction gap junction basal ectoplasmic specialization and desmosome-like junction give rise altogether to the blood-testis barrier (BTB)The BTB divides the seminiferous epithelium into basal and adluminal compartments In this last the apical ectoplasmic specialization (aEs)is established aEs is the unique type of anchoring junction between Sertoli cell and elongatingelongated spermatids It undergoes cycles ofassemblingdisassembling At spermiation it disassembles definitely to allow sperm release

contribute to create the blood-testis barrier (BTB) The BTBphysically divides the seminiferous epithelium in two com-partments that is a basal compartmentwhere spermatogoniaand spermatocytes reside and an adluminal compartmentwhere spermatids differentiate to develop into spermatozoa(Figure 1) [16 17] The establishment of the BTB is funda-mental for a successful spermatogenesis its integrity has tobemaintained throughout the entire spermatogenesis [18 19]The BTB provides in fact an immunological barrier to thedeveloping male germ cells it sequesters postmeiotic germcells from the systemic circulation thus preventing the pro-duction by the host of antibodies against spermatid-specificantigens whose expression is restricted to spermiogenesisonly [20] The BTB likely functions also as a gatekeeperenabling only the passage through the seminiferous epithe-lium of selected substancesmolecules of support to germcells The molecular components and the functions of the

BTB have been extensively reviewed (for excellent reviewssee [12 17 21]) it will be no longer discussed here

Conversely this brief review will focus around the apicalES (aES) restricted to Sertoli-postmeiotic germ cells at theadluminal compartment Differently from bES aES does notcoexist with other junctions the aES is the only junctionaldevice that sustains the association between Sertoli and elon-gatingelongated spermatids (from step 8 of differentiation)until the early phase of spermiation when it disassembles(Figure 1) [13 22ndash24]

2 Apical Ectoplasmic Specialization

The aES is the best known anchoring junction in the testisSeveral studies have led to a significant improvement of ourknowledge about its molecular architecture and molecular

BioMed Research International 3

components On the basis of such studies the aES is emergedas a peculiar anchoring junction being formed by structuralcomponents generally found in somatic adherens junctions(the cadherinscatenins and nectinsafadin complexes) tightjunctions (such as Jam-C molecules) and focal contacts (theintegrinlaminin complex) (Figure 2) [14 25 26] This highheterogeneity is thought to permit that the aES accomplishesits multifunctional role in supporting spermiogenesis Indetails the aES makes the migration possible concomitantlywith the differentiation of spermatids across the seminif-erous epithelium Moreover the aES could contribute topositioning elongating spermatids with their heads pointedtowards the basal compartment It is to notice that aES isfirst assembled within the seminiferous epithelium exactlywhen spermatids begin to loss their spherical shape tobecome a polarized cell (stage 8) [13 14 25] Finally theaES maintains spermatids attached to Sertoli cells untilthese are differentiated and ready to be released into thelumen [13 23 24] It follows that aES has to undergo rapidcycles of assembly and disassembly concomitantly with theprogression of spermiogenesis and that at spermiation thebreakage at cell-cell contacts is definitive The dynamic ofthese cycles must be finely and timely regulated Despitemany efforts the mechanisms governing the aES remod-eling during spermiogenesisspermiation remain howeverobscure

Herein we address attention on how aES dynamiccould be regulated In particular taking into considerationnew experimental evidence provided independently frommore laboratories we discuss a model of regulation ofaES assemblydisassembly upon the grounds of findings weobtained from an animal model that we generated appo-sitely to inactivate the small Ras-like GTPase Rap1 [27]Importantly it is to underline that this model provides thefirst genetic link between Rap1 defects and male infertil-ity the Rap1[S17N] mutation is resulted to be instrumen-tal in revealing the cAMP-Epac-Rap1extracellular signal-regulated pathway that governs the spermatid-Sertoli celladhesion at aES Moreover it is worth of mention to recallattention on the fact that the central cell of our model is thedifferentiating spermatid So far most works about the aESregulation highlight putativemechanisms operating in Sertolicells relegating spermatids to a role of merely spectatorsHowever the ldquoactorsrdquo that are involved in cell-to-cell contactare at least two Consequently our model offers a new pointof view to investigate about aES dynamic that is to considerthat also germ cells could be actively engaged

3 Rap1 Regulates aES DynamicExperimental Evidence

Rap1 is a member of the family of Ras-like small G proteins[28] accordingly it switches between an active conformationbound to the GTP and an inactive one bound to the GDPThecycle between the two alternative states is coordinated by theguanine nucleotide exchange factors (GEFs) the activatorsthat allow the binding with GTP and the GTPase activatingproteins (GAPs) that enhance the hydrolysis of bound GTP

thus leading to Rap1 deactivation [29 30] Rap1 functions asa positional signal and organizer of cell architecture it followsthat this GTPase is placed upstream signalling pathways thatregulate diverse cellular processes including morphogenesis[31 32] cell differentiation [33] cytoskeletal organization[34] cytokinesis [35] exocytosisendocytosis [36] synapticplasticity [37] and cell-cell adhesion [30] As to this lastaspect of Rap1 biology a growing experimental evidencein the last years has allowed to highlight some aspects ofRap1 action in controlling integrin-based as well as cadherin-based junctional systems in particular Rap1 has been shownto regulate the levels of E-cadherin and VE-cadherin atthe plasma membrane of epithelial and endothelial cellsrespectively [38ndash42]

Rap1 was first detected in the testis in 2000 [43] Itis expressed by germ cells throughout spermatogenesis inspermatids in particular it was immunoprecipitated as acomponent of the signaling complex formed by the serine-threonine kinase B-Raf and the molecular adaptor 14-3-3theta protein [43] To verify the role of Rap1 in vivo in the pro-cess of sperm differentiation we developed a mouse modelTransgenic mice that express a dominant negative mutant ofRap1 (iRap1) were generated to have the expression of themutant Rap1 variant selectively only in the postmeiotic germcells iRap1 was put under the control of the haploid-specificProtamine-1 promoter [27] The phenotype of the mutantmice resulted in a derailment of spermiogenesis due to ananomalous release of immature round spermatids withinthe tubule lumen and low sperm counts These findingsaddressed the research to point up towards the search of Rap1-regulated adhesionmolecules leading to the discovery of VE-cadherin and of its epithelial cycle stage specific expression[27]

The high dynamicity of aES renders it as one of themost flexible cell-cell junctions in mammalian tissue maybecomparable to the better characterized adherens junction atthe endothelial cell barrier This last is known to be a highlydynamic structure it maintains the integrity of the endothe-lium but it is also involved in the control of permeabilityleukocyte diapedesis and more generally speaking vascularhomeostasis [44] The stabilization of endothelial adherensjunctions relies on the stabilization at the plasma membraneof the vascular endothelial cadherin (VE-cadherin) throughactivation of Rap1 by the cAMP sensorRap1-GEF Epac [45]It is in fact widely known that the increase of intracellularcAMP leads to the formation of circumferential actin bundlesthat support cadherins at adherens junctions this occursthrough Epac-activated Rap1 Similarly Rap1 is involvedin the formation of E-cadherin-based cell-cell adhesionsin epithelial cells [38 40 41] However Aivatiadou et al[27] found that not only VE-cadherin is expressed in thetestis but it localizes at aES level exhibiting a patternof expression that follows aES formation and function itappears in the adluminal compartment when aESs are beingformed and disappears at spermiation with the exception ofthe intense staining of the soma of Sertoli cells at the basalcompartment Interestingly in iRapmutantmice that expressa dominant negative Rap1 VE-cadherin is more looselylinked to cytoskeleton and partially tyrosine phosphorylated


Sertoli cellSpermatid

VE-cadherin

Nectin-2

Nectin-3

Jam-C

p120-catenin

aPKC

Afadin

Par6Par3

Cdc42Sertoli cell

Afadin

Actin

fila

men

t

Jam-B


aEs stabiliz

ation

aES assembly

Cell polarization

120572-c

aten

in

120573-catenin

Figure 2 Molecular components at aES level The picture shows junctional molecules and associated proteins present at aES as discussedhere attention is particularly devoted to junctional complexes on the spermatid membrane As suggested in the text an initial Sertoli-spermatid contact may be established by nectins engagement and then VE-cadherincatenin complexes contribute to the aES stabilizationIn accordance with the literature the adhesion molecule Jam-C could be involved in spermatid polarizationpositioning by recruiting thePar6Par3aPKCCdc42 polarity complex

two conditions known to be related to impairment of cell-cell adhesions [27 41] At last we remember that the adaptorproteins 120572- 120573-catenins essential for linking the cadherins toactin filaments [46] and p120-catenin are expressed in bothSertoli and germ cells [47] Similarly germ cells express alsoafadin [48] Afadin is a scaffold protein containing an actin-binding and RasRap-binding domain [29 49] that has beenreported to regulate the cyclical activationinactivation ofRap1 andRhoA [50] In endothelial and epithelial cells afadinis involved in Rap1-dependent assembly of cadherins-basedadherens junctions (AJs) [40 51 52] The Rap1-GTPafadincomplex mediates the recruitment of p120-catenin to theplasma membrane [51 52] thus stabilizing VE-cadherin andprotecting it from endocytosis [53]

The iRap1 animal model by Aivatiadou et al [27] clearlydemonstrated that Rap1 is involved in the regulation of aESjunction dynamic However how Rap1 exerts its control andwhat are its protein targets have not been yet dissectedVery likely testis VE-cadherin is the adhesion receptortarget of Rap1 in spermatids this however does not meanthat VE-cadherin is the only one Here we suggest inaddition to VE-cadherin another putative candidate nectinNectins belong to the superfamily of Ca2+-independentimmunoglobulins that comprises at least four members [49]they are able to form both homophilic and heterophilictrans-interactions [49] Nectins have been shown at aESsmore specifically nectin-2 on the Sertoli membrane trans-interacts with nectin-3 on the spermatid membrane [54] Ithas been reported that the nectin-2nectin-3 complex at aESis stabilized by afadin that connects the complex to the actinfilaments [54] Since afadin could connect with both nectin-based and cadherin-based junctional systems Rap1 could

represent the central regulatory link between these two aESstructural complexes Considering that aESs undergo cyclesof assembly and disassembly and that Rap1 mediates boththe de novo formation and the reestablishment of adherensjunctions [38 55] the following hypothesis for future experi-mental research could be suggestedThat is at the assemblingnectins are first engaged at aES recruiting afadin that onits own is involved in activation of Rap1 this leads to anaccumulation of VE-cadherin at the plasma membrane withthe result of strengthening of the junction The nectinsVE-cadherin adhesion molecules have already been described tobe able to connect physically and functionally in endothelialcell systems [56 57]

4 Rap1 as an Organizer ofSpermatid Polarization at aES

Rap1 action is accomplished through the cooperation ofdifferent signaling pathways involving several effectors [3258 59] In its central role of positional signal and organizerof cell architecture Rap1 governs the reorganization of actincytoskeleton [34 60 61] The great plasticity of the aESrequires a rapid rearrangement of actin cytoskeleton it isnot surprising if Rap1 could emerge as a regulator of thiscytoskeleton at aES CDC42 is another Ras-like small GTPasethat belongs to the family of Rho-GTPases [62ndash64] andCDC42 is a Rap1 effector In epithelial as well as endothelialcells Epac-activated Rap1 induces CDC42 activation thisleads to a reorganization of actin cytoskeleton resulting in theformation of circumferential actin bundles and consequentlyin the stability of E-cadherinVE-cadherin-based cell-cell


cAMP

Epac

Rap1

Cdc42

cAMP

Epac

Rap1

RA-RhoGAPRA-RhoGAP

Cdc42


Sertoli cell

Rap1 activation

Rho

Rap1 inactivation

Rho

Rap1-GAP

aEs stabilization aES destabilization

(prolonged TGF120573)

(short TGF120573)VE-cad

Afad

in

Afa

din

Nectin

-3 Par

com

plex

Jam-C

Actin

Actin

p120

Figure 3 The proposed model of regulation of aES dynamic The aES structuringrestructuring is governed by a coordinated crosstalkbetween Ras-like small GTPases among which Rap1 is the central core Under conditions that favor Sertoli-spermatid contacts (TGF120573 ishere suggested as one of the putative candidates that promotes the cAMP signaling for establishment of cell-cell contact) the triggered cAMPelevation leads to Epac-mediated Rap1 activation Rap1 action stabilizes aES junctions acting on both nectinafadin and VE-cadherincatenincomplexes as well as on CDC42 thus promoting actin filament organization Moreover activated Rap1 acts on another Rap1 effector namelyRA-RhoGAP so that the activity of Rho-GTPase is switched offConversely under conditions that promote aESdestabilization (here suggestedas a short exposition to TGF120573) the consequent decrease in cAMP level leads to Rap1 deactivation with the downstream effects on the junctionstability and F-actin organization concomitantly RA-RhoGAP is not activated and the Rho-driven disassembling of aES could take placeAll the proteins discussed here are known to be expressed in male germ cells See text for details and further discussion

adhesions [34 45 60] Since CDC42 is expressed in differ-entiating spermatids [65 66] it is possible to speculate thatRap1-mediated CDC42 activation is one of the mechanismsthat stabilize cell-cell contacts at aESs Not only but CDC42may be the Rap1 effector through which Rap1 acting as acritical regulator of cell polarization [67] controls spermatidpolarization an event for which the contribution of aES hasbeen evoked more times in the seminiferous epitheliumCdc42 in fact is known to work in epithelial cells in concertwith the Par-based polarity protein complex to establishthe apicobasal cell polarity [68 69] Interestingly in sper-matids the Par6Cdc42aPKC complex has been shown to berecruited to the plasma membrane by Jam-C a junctionaladhesion molecule found at aES level [65 70] Gliki et al[65] attributed to Jam-C the role of assembling the cellpolarity complex and consequently of promoting spermatidpolarization However the pathway though which Jam-Ccould fulfill such functions was not dissected In endothelialcells Jam-C regulates vascular endothelial permeability bymodulating VE-cadherin-mediated cell-cell contacts [71] Inparticular the loss of Jam-C expression by Jam-C knockdownresults in stabilization of VE-cadherin-mediated adhesionin a Rap1-dependent manner It follows that the questionof Jam-C and Par6Cdc42aPKC complex in differentiatingspermatids deserves a deeper investigation Again Rap1

may emerge as the central regulator that supervises bothaES assemblydisassembly and spermatid polarity in a newsystem the spermatid-Sertoli cell adhesion system In thisregard it is to notice that just the VE-cadherin-based AJshave been reported to be essential to establish cell polarityhere it is in fact recruited the Rap1-activated cell polar-ity complex in endothelia [72] So it is not to excludethat Rap1 could mediate spermatid polarization not onlythrough the Jam-Cpolarity complex but also through theVE-cadherinpolarity complex system

5 Rap1 Rho and the Disassembling of aES

Rho belongs as CDC42 and Rac1 to the family of RhoGTPases and is involved in the dynamics of F-actin structuresthus influencing cell shape and assembly of AJs The bestcharacterized Rho isoforms are RhoA RhoB and RhoC[73 74] RhoA and RhoB have been reported in testis andspermatozoa [66] While CDC42 and Rac1 are known to actas Rap1 effectors that is downstream the activated Rap1 RhoGTPase is best known to counteract the action of Rap1 [2734 75] For example activation of the Rho GTPase pathwaydetermines endothelial cell hyperpermeability and couldlead to endothelial barrier disruption [75 76] Accordingly


overexpression of a constitutively active mutant of Rap1results in activation of Rac1 and intriguingly inactivationof RhoA [50] As already noticed with few exceptionsmembers of the Ras-like GTPase super-family cycle betweenan active and inactive state The continuous cycling betweenthe two states is tightly controlled by a number of regulatoryproteins that specify where and for how long the signal isldquoonrdquo and which cellular function is modulated In the caseof cell adhesion for each cellular process triggered by cell-cell contacts multiple GTPases must be dynamically turnedldquoonrdquo or ldquooffrdquo [34 50 75] This ldquoturningrdquo is facilitated byGEFs and GAPs respectively So far several GEFs and GAPshave been described tomodulate the organization molecularcomposition and function of adhesive complexes in differentcell types In endothelial cells the second messenger cAMPinduces barrier protective responses against thrombin orinflammatory mediators [77 78] The Rap1 GEFs that aresensors of cAMP elevation are known as Epac (exchangeprotein activated by cAMP) of which there are two variantsEpac1 and Epac2 [79ndash81] Rap1 however could be activatedalso by other GEFs such as C3G PDZ-GEFs and CalDAGs[59 82 83] Still referring to the endothelial cell AJs Birukovaet al [75] have shown that the Rap1 PDZ-GEF cooperateswith Epac to maintain junction integrity more specificallythe PDZ-GEF is involved mainly in Rap1 activation underresting conditions [45] while Epacs isare necessary tofurther tighten cell-cell contacts [45] Both Epac1 and Epac2have been found in mouse testis and male germ cells [8084] Similar to the GEFs there are various Rap-GAPs thatare specifically targeted to different molecular complexes atvarious cellular locations [59] These GAPs may reverse thedynamic processes controlled by activated Rap1 Among thebest characterized Rap1-GAPs there are Rap1-GAP12 Spa-1 and SPAR123 [59] so far however experimental evidencefor Rap1-GAPs in the testis is still lacking

This is not the case on the contrary for RhoGAPsAivatiadou et al [80] reported that male germ cells expressRA-RhoGAP RA-RhoGAP is a RhoGAP that possesses a RAdomain through which it binds to Epac-activated Rap1 thusacting as a Rap1 effector and transductor of signal from Rap1to Rho [85] Indeed Aivatiadou et al [80] showed also thatin isolated spermatogenic cells after stimulation with 8-CPT(a membrane-permeable analogue of cAMP) Epac-activatedRap1 colocalizes with RA-RhoGAP It follows that male germcells have the equipment of signaling molecules includingactivators and effectors through which activated Rap1 couldsuppress the action of Rho

At this point if Rap1 and Rho are likely the Ras-like GTPases that govern aES dynamic a key questionconcerns the signals responsible for the Rap1Rho activa-tiondeactivation at aES Before the conclusion of this briefreview we want to provide a further suggestion towards thedirection for this putative signaling molecule Transform-ing growth factor-1205731 (TGF-1205731) functions in diverse cellularprocesses such as tissue differentiation and cell migrationRecent experimental evidence on signaling that governsmonocyte adhesion and chemotaxis [86] has revealed thatTGF-1205731 triggers cAMP elevation leading to Rap1 activationvia Epac not only this but also this Rap1 activation on its

own results in Rho inactivation through the Rap1-dependentRhoGAP In other words prolonged TGF-1205731-treated cellsproduce cAMP which activates sequentially Epac Rap1 andRap1-dependent RhoGAP resulting in suppression of Rhoand macrophage migration TGF-1205731 is produced in the testisby both germ cells and Sertoli cells [87] TGF-1205731 may thusresult to be crucial for the restructuring of aES

Conclusively here we provide a model (Figure 3) for themechanisms by which Rap1 could potentially regulate aESdynamic It is to remark that here we took into considerationdeliberately only spermatids that is the cells so far ratherneglected under this context Restructuring of aES junctionis thought to be dependent on a highly coordinated net-work of mechanisms of activationdeactivation of Ras-likeGTPases that has Rap1 as its central hub and the Rho-familyGTPases as downstream Rap1-effectorsantagonists Rap1action results in the assemblystabilizationreestablishmentof aES junctions whereas Rho drives their disassemblinginterestingly the functional Rap1Rho interaction is proposedto be vice-versa reciprocal Obviously some aspects of thesuggested regulation of aES dynamic need to be verified andare waiting for the experimental validation

6 Conclusion

Male infertility is one of the health problems worldwideSeveral defects responsible formale infertility are still unclearmostly due to our poor understanding of molecular mech-anisms that regulate sperm production and release fromthe testis the maturation and transit of the sperm throughthe male and female tracts and the events essential forfertilization Because we do not understand entirely thesemolecular processes we cannot diagnose correctly the causesof male infertility Upon the grounds of the phenotype thatcharacterizes the unique animal model developed so far toinvestigate in vivo about the nature of the signaling involvedin the regulation of spermatid-Sertoli cell junctions [27]here we propose two interconnected mechanisms that couldunravel the question of the regulation of a highly dynamicand essential junction like the aES is

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C P Leblond and Y Clermont ldquoDefinition of the stages of thecycle of the seminiferous epithelium in the ratrdquo Annals of theNew York Academy of Sciences vol 55 no 4 pp 548ndash573 1952

[2] E F Oakberg ldquoA description of spermiogenesis in the mouseand its use in analysis of the cycle of the seminiferous epitheliumand germ cell renewalrdquo The American Journal of Anatomy vol99 no 3 pp 391ndash413 1956

[3] L Russell R A Ettlin A P Sinha Hikim and E J CleggHistological andHistopathological Evaluation of the Testis CacheRiver Press Clearwater Fla USA 1990


[4] R A Hess and L R de Franca ldquoSpermatogenesis and cycleof the seminiferous epitheliumrdquo Advances in ExperimentalMedicine and Biology vol 636 pp 1ndash15 2008

[5] M D Griswold ldquoThe central role of Sertoli cells in spermato-genesisrdquo Seminars in Cell and Developmental Biology vol 9 no4 pp 411ndash416 1998

[6] M Godet O Sabido J Gilleron and P Durand ldquoMeioticprogression of rat spermatocytes requires mitogen-activatedprotein kinases of Sertoli cells and close contacts between thegerm cells and the Sertoli cellsrdquoDevelopmental Biology vol 315no 1 pp 173ndash188 2008

[7] L Russell ldquoMovement of spermatocytes from the basal to theadluminal compartment of the rat testisrdquoThe American Journalof Anatomy vol 148 no 3 pp 313ndash328 1977

[8] L D Russell and R N Peterson ldquoSertoli cell junctionsmorphological and functional correlatesrdquo International Reviewof Cytology vol 94 pp 177ndash211 1985

[9] D D Mruk and C Y Cheng ldquoSertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell move-ment in the seminiferous epithelium during spermatogenesisrdquoEndocrine Reviews vol 25 no 5 pp 747ndash806 2004

[10] L Su D D Mruk and C Y Cheng ldquoRegulation of the blood-testis barrier by coxsackievirus and adenovirus receptorrdquo TheAmerican Journal of Physiology vol 303 no 8 pp C843ndashC8532012

[11] K Weider M Bergmann and R Brehm ldquoConnexin 43 itsregulatory role in testicular junction dynamics and spermato-genesisrdquoHistology and Histopathology vol 26 no 10 pp 1343ndash1352 2011

[12] C Y Cheng E W Wong P P Lie M W Li D D MrukH H Yan et al ldquoRegulation of blood-testis barrier dynamicsby desmosome gap junction hemidesmosome and polarityproteins an unexpected turn of eventsrdquo Spermatogenesis vol1 no 2 pp 105ndash115 2011

[13] A W Vogl D C Pfeiffer D Mulholland G Klmel and JGuttman ldquoUnique and multifunctional adhesion junctions inthe testis ectoplasmic specializationsrdquoArchives of Histology andCytology vol 63 no 1 pp 1ndash15 2000

[14] E W P Wong D D Mruk and C Y Cheng ldquoBiology andregulation of ectoplasmic specialization an atypical adherensjunction type in the testisrdquo Biochimica et Biophysica Acta vol1778 no 3 pp 692ndash708 2008

[15] DDMruk andCYCheng ldquoDesmosomes in the testismovinginto an unchartered territoryrdquo Spermatogenesis vol 1 no 1 pp47ndash51 2011

[16] M Dym and D W Fawcett ldquoThe blood-testis barrier in therat and the physiological compartmentation of the seminiferousepitheliumrdquo Biology of Reproduction vol 3 no 3 pp 308ndash3261970

[17] C-H Wong and C Y Cheng ldquoThe blood-testis barrier itsbiology regulation and physiological role in spermatogenesisrdquoCurrent Topics in Developmental Biology vol 71 pp 263ndash2962005

[18] J Grima and C Y Cheng ldquoTestin induction the role of cyclic3101584051015840-adenosine monophosphateprotein kinase A signaling inthe regulation of basal and lonidamine-induced testin expres-sion by rat Sertoli cellsrdquo Biology of Reproduction vol 63 no 6pp 1648ndash1660 2000

[19] N P Y Chung and C Y Cheng ldquoIs cadmium chloride-inducedinter-Sertoli tight junction permeability barrier disruption a

suitable in vitromodel to study the events of junction disassem-bly during spermatogenesis in the rat testisrdquo Endocrinologyvol 142 no 5 pp 1878ndash1888 2001

[20] K W Beagley Z L Wu M Pomering and R C JonesldquoImmune responses in the epididymis implications forimmunocontraceptionrdquo Journal of Reproduction and Fertilityvol 53 pp 235ndash245 1998

[21] C Yan Cheng and D D Mruk ldquoThe blood-testis barrier and itsimplications for male contraceptionrdquo Pharmacological Reviewsvol 64 no 1 pp 16ndash64 2012

[22] L Russell ldquoObservations on rat Sertoli ectoplasmic (junctional)specializations in their association with germ cells of the rattestisrdquo Tissue and Cell vol 9 no 3 pp 475ndash498 1977

[23] L D Russell ldquoMorphological and functional evidence forSertoli-germ cell relationshipsrdquo inThe Sertoli Cell L D Russelland M D Griswold Eds pp 365ndash390 Cache River PressClearwater Fla USA 1993

[24] J S Young J AGuttmanK SVaid andAWayneVogl ldquoTubu-lobulbar complexes are intercellular podosome-like structuresthat internalize intact intercellular junctions during epithelialremodeling events in the rat testisrdquo Biology of Reproduction vol80 no 1 pp 162ndash174 2009

[25] D D Mruk B Silvestrini and C Y Cheng ldquoAnchoringjunctions as drug targets role in contraceptive developmentrdquoPharmacological Reviews vol 60 no 2 pp 146ndash180 2008

[26] I A Ropera B Bilinska C Y Cheng and D D Mruk ldquoSertoli-germ cell junctions in the testis a review of recent datardquoPhilosophical Transactions of the Royal Society B vol 365 no1546 pp 1593ndash1605 2010

[27] E Aivatiadou E Mattei M Ceriani L Tilia and G BerrutildquoImpaired fertility and spermiogenetic disorders with loss ofcell adhesion in male mice expressing an interfering Rap1mutantrdquo Molecular Biology of the Cell vol 18 no 4 pp 1530ndash1542 2007

[28] H Kitayama Y Sugimoto TMatsuzaki Y Ikawa andMNodaldquoA ras-related gene with transformation suppressor activityrdquoCell vol 56 no 1 pp 77ndash84 1989

[29] M R H Kooistra N Dube and J L Bos ldquoRap1 a key regulatorin cell-cell junction formationrdquo Journal of Cell Science vol 120no 1 pp 17ndash22 2007

[30] W-J Pannekoek M R H Kooistra F J T Zwartkruis and JL Bos ldquoCell-cell junction formation the role of Rap1 and Rap1guanine nucleotide exchange factorsrdquo Biochimica et BiophysicaActa vol 1788 no 4 pp 790ndash796 2009

[31] M Ji and O M Andrisani ldquoHigh-level activation of cyclicAMP signaling attenuates bone morphogenetic protein 2-induced sympathoadrenal lineage development and promotesmelanogenesis in neural crest culturesrdquoMolecular and CellularBiology vol 25 no 12 pp 5134ndash5145 2005

[32] M Chrzanowska-Wodnicka ldquoDistinct functions for Rap1 sig-naling in vascular morphogenesis and dysfunctionrdquo Experi-mental Cell Research vol 319 no 15 pp 2350ndash2359 2013

[33] L Li J S Kim and V A Boussiotis ldquoRap1A regulates gen-eration of T regulatory cells via LFA-1-dependent and LFA-1-independent mechanismsrdquo Cellular Immunology vol 266 no1 pp 7ndash13 2010

[34] K Ando S Fukuhara T Moriya Y Obara N Nakahata andN Mochizuki ldquoRap1 potentiates endothelial cell junctions byspatially controlling myosin II activity and actin organizationrdquoJournal of Cell Biology vol 202 no 6 pp 901ndash916 2013


[35] V T Dao A G Dupuy O Gavet E Caron and J deGunzburg ldquoDynamic changes in Rap1 activity are required forcell retraction and spreading during mitosisrdquo Journal of CellScience vol 122 no 16 pp 2996ndash3004 2009

[36] K W van Hooren E L van Agtmaal M Fernandez-BorjaJ A van Mourik J Voorberg and R Bierings ldquoThe Epac-Rap1 signaling pathway controls cAMP-mediated exocytosis ofWeibel-Palade bodies in endothelial cellsrdquo Journal of BiologicalChemistry vol 287 no 29 pp 24713ndash24720 2012

[37] R L Stornetta and J J Zhu ldquoRas and Rap signaling in synapticplasticity and mental disordersrdquoNeuroscientist vol 17 no 1 pp54ndash78 2011

[38] C Hogan N Serpente P Cogram et al ldquoRap1 regulates theformation of E-cadherin-based cell-cell contactsrdquo Molecularand Cellular Biology vol 24 no 15 pp 6690ndash6700 2004

[39] T Hoshino T Sakisaka T Baba T Yamada T Kimura and YTakai ldquoRegulation of E-cadherin endocytosis by nectin throughafadin Rap1 and p120ctnrdquo Journal of Biological Chemistry vol280 no 25 pp 24095ndash24103 2005

[40] T Sato N Fujita A Yamada et al ldquoRegulation of the assemblyand adhesion activity of E-cadherin by nectin and afadin for theformation of adherens junctions inMadin-Darby canine kidneycellsrdquo Journal of Biological Chemistry vol 281 no 8 pp 5288ndash5299 2006

[41] S Fukuhara A Sakurai A Yamagishi K Sako and N Moe-hizuki ldquoVascular endothelial cadherin-mediated cell-cell adhe-sion regulated by a small GTPase Rap1rdquo Journal of Biochemistryand Molecular Biology vol 39 no 2 pp 132ndash139 2006

[42] K Noda J Zhang S Fukuhara S Kunimoto M Yoshimuraand N Mochizuki ldquoVascular endothelial-cadherin stabilizes atcell-cell junctions by anchoring to circumferential actin bundlesthrough 120572- and 120573-catenins in cyclic AMP-Epac-Rap1 signal-activated endothelial cellsrdquoMolecular Biology of the Cell vol 21no 4 pp 584ndash596 2010

[43] G Berruti ldquoA novel Rap1B-Raf14-3-3 120579 protein complex isformed in vivo during the morphogenetic differentiation ofpostmeiotic male germ cellsrdquo Experimental Cell Research vol257 no 1 pp 172ndash179 2000

[44] E Dejana ldquoEndothelial cell-cell junctions happy togetherrdquoNature ReviewsMolecular Cell Biology vol 5 no 4 pp 261ndash2702004

[45] W-J Pannekoek J J G van Dijk O Y A Chan et al ldquoEpac1and PDZ-GEF cooperate in Rap1mediated endothelial junctioncontrolrdquo Cellular Signalling vol 23 no 12 pp 2056ndash2064 2011

[46] C Kintner ldquoRegulation of embryonic cell adhesion by thecadherin cytoplasmic domainrdquo Cell vol 69 no 2 pp 225ndash2361992

[47] N P Y Lee D Mruk W M Lee and C Y Cheng ldquoIsthe cadherincatenin complex a functional unit of cell-cellactin-based adherens junctions in the rat testisrdquo Biology ofReproduction vol 68 no 2 pp 489ndash508 2003

[48] H H N Yan D D Mruk W M Lee and C Y Cheng ldquoEcto-plasmic specialization a friend or a foe of spermatogenesisrdquoBioEssays vol 29 no 1 pp 36ndash48 2007

[49] Y Takai W Ikeda H Ogita and Y Rikitake ldquoThe immuno-globulin-like cell adhesion molecule nectin and its associatedprotein afadinrdquo Annual Review of Cell and DevelopmentalBiology vol 24 pp 309ndash342 2008

[50] M Miyata Y Rikitake M Takahashi et al ldquoRegulation byafadin of cyclical activation and inactivation of Rap1 Rac1 andRhoA small G proteins at leading edges of moving NIH3T3

cellsrdquo Journal of Biological Chemistry vol 284 no 36 pp24595ndash24609 2009

[51] H Tawa Y Rikitake M Takahashi et al ldquoRole of afadin in vas-cular endothelial growth factor-and sphingosine 1-phosphate-induced angiogenesisrdquo Circulation Research vol 106 no 11 pp1731ndash1742 2010

[52] A A Birukova P Fu T Wu et al ldquoAfadin controlsp120-catenin-ZO-1 interactions leading to endothelial barrierenhancement by oxidized phospholipidsrdquo Journal of CellularPhysiology vol 227 no 5 pp 1883ndash1890 2012

[53] K Xiao J Garner K M Buckley et al ldquop120-catenin regulatesclathrin-dependent endocytosis of VE-cadherinrdquo MolecularBiology of the Cell vol 16 no 11 pp 5141ndash5151 2005

[54] K Ozaki-Kuroda H Nakanishi H Ohta et al ldquoNectin couplescell-cell adhesion and the actin scaffold at heterotypic testicularjunctionsrdquo Current Biology vol 12 no 13 pp 1145ndash1150 2002

[55] E S Wittchen R A Worthylake P Kelly P J Casey L AQuilliam and K Burridge ldquoRap1 GTPase inhibits leukocytetransmigration by promoting endothelial barrier functionrdquoJournal of Biological Chemistry vol 280 no 12 pp 11675ndash116822005

[56] T Fukuyama H Ogita T Kawakatsu et al ldquoInvolvement of thec-Src-Crk-C3G-Rap1 signaling in the nectin-induced activationof Cdc42 and formation of adherens junctionsrdquo Journal ofBiological Chemistry vol 280 no 1 pp 815ndash825 2005

[57] D Herr H M Fraser R Konrad I Holzheu R Kreienbergand C Wulff ldquoHuman chorionic gonadotropin controls lutealvascular permeability via vascular endothelial growth factor bydown-regulation of a cascade of adhesion proteinsrdquo Fertility andSterility vol 99 no 6 pp 1749ndash1758 2013

[58] S Citi D Spadaro Y Schneider J Stutz and P PulimenoldquoRegulation of small GTPases at epithelial cell-cell junctionsrdquoMolecularMembrane Biology vol 28 no 7-8 pp 427ndash444 2011

[59] M Gloerich and J L Bos ldquoRegulating Rap small G-proteins intime and spacerdquo Trends in Cell Biology vol 21 no 10 pp 615ndash623 2011

[60] M R H Kooistra M Corada E Dejana and J L Bos ldquoEpac1regulates integrity of endothelial cell junctions through VE-cadherinrdquo FEBS Letters vol 579 no 22 pp 4966ndash4972 2005

[61] A A Birukova D Burdette N Moldobaeva J Xing P Fuand K G Birukov ldquoRac GTPase is a hub for protein kinase Aand Epac signaling in endothelial barrier protection by cAMPrdquoMicrovascular Research vol 79 no 2 pp 128ndash138 2010

[62] A B Jaffe and A Hall ldquoRho GTPases biochemistry andbiologyrdquo Annual Review of Cell and Developmental Biology vol21 pp 247ndash269 2005

[63] KWennerberg and C J Der ldquoRho-family GTPases itrsquos not onlyRac and Rho (and I like it)rdquo Journal of Cell Science vol 117 no8 pp 1301ndash1312 2004

[64] J Melendez M Grogg and Y Zheng ldquoSignaling role of Cdc42in regulating mammalian physiologyrdquo Journal of BiologicalChemistry vol 286 no 4 pp 2375ndash2381 2011

[65] G Gliki K Ebnet M Aurrand-Lions B A Imhof and RH Adams ldquoSpermatid differentiation requires the assemblyof a cell polarity complex downstream of junctional adhesionmolecule-Crdquo Nature vol 431 no 7006 pp 320ndash324 2004

[66] R Baltierrez-Hoyos A L Roa-Espitia and E O Hernandez-Gonzalez ldquoThe association between CDC42 and caveolin-1is involved in the regulation of capacitation and acrosomereaction of guinea pig andmouse spermrdquoReproduction vol 144no 1 pp 123ndash134 2012


[67] Y Jossin ldquoPolarization of migrating cortical neurons by Rap1and N-cadherin revisiting the model for the reelin signalingpathwayrdquo Small GTPases vol 2 no 6 pp 322ndash328 2011

[68] D P Welchman L D Mathies and J Ahringer ldquoSimilarrequirements for CDC-42 and the PAR-3PAR-6PKC-3 com-plex in diverse cell typesrdquo Developmental Biology vol 305 no1 pp 347ndash357 2007

[69] K P Harris and U Tepass ldquoCdc42 and vesicle trafficking inpolarized cellsrdquo Traffic vol 11 no 10 pp 1272ndash1279 2010

[70] E W P Wong D D Mruk W M Lee and C Y ChengldquoPar3Par6 polarity complex coordinates apical ectoplasmicspecialization and blood-testis barrier restructuring duringspermatogenesisrdquo Proceedings of the National Academy of Sci-ences of the United States of America vol 105 no 28 pp 9657ndash9662 2008

[71] V V Orlova M Economopoulou F Lupu S Santoso and TChavakis ldquoJunctional adhesion molecule-C regulates vascularendothelial permeability bymodulatingVE-cadherin-mediatedcell-cell contactsrdquo Journal of Experimental Medicine vol 203no 12 pp 2703ndash2714 2006

[72] M G Lampugnani F Orsenigo N Rudini et al ldquoCCM1regulates vascular-lumen organization by inducing endothelialpolarityrdquo Journal of Cell Science vol 123 no 7 pp 1073ndash10802010

[73] C L Hutchinson P N Lowe S H McLaughlin H R Mottand D Owen ldquoDifferential binding of RhoA RhoB andRhoC to protein kinase C-related kinase (PRK) isoforms PRK1PRK2 and PRK3 PRKs have the highest affinity for RhoBrdquoBiochemistry vol 52 no 45 pp 7999ndash8011 2013

[74] A J Ridley ldquoRhoA RhoB and RhoC have different roles incancer cell migrationrdquo Journal of Microscopy vol 251 no 3 pp242ndash249 2013

[75] A A Birukova X Tian Y Tian K Higginbotham and KG Birukova ldquoRap-afadin axis in control of Rho signaling andendothelial barrier recoveryrdquoMolecular Biology of the Cell vol24 no 17 pp 2678ndash2688 2013

[76] X Cullere S K Shaw L Andersson J Hirahashi F W Lus-cinskas and T N Mayadas ldquoRegulation of vascular endothelialbarrier function by Epac a cAMP-activated exchange factor forRap GTPaserdquo Blood vol 105 no 5 pp 1950ndash1955 2005

[77] A A Birukova T Zagranichnaya P Fu et al ldquoProstaglandinsPGE2 and PGI2 promote endothelial barrier enhancement viaPKA- and Epac1Rap1-dependent Rac activationrdquo ExperimentalCell Research vol 313 no 11 pp 2504ndash2520 2007

[78] N V Bogatcheva J G Garcia and A D Verin ldquoMolecularmechanisms of thrombin-induced endothelial cell permeabil-ityrdquo Biochemistry vol 67 no 1 pp 75ndash84 2002

[79] H Kawasaki G M Springett N Mochizuki et al ldquoA family ofcAMP-binding proteins that directly activate Rap1rdquo Science vol282 no 5397 pp 2275ndash2279 1998

[80] E AivatiadouM Ripolone F Brunetti and G Berruti ldquocAMP-Epac2-mediated activation of Rap1 in developing male germcells RA-RhoGAP as a possible direct down-stream effectorrdquoMolecular Reproduction and Development vol 76 no 4 pp407ndash416 2009

[81] M Gloerich and J L Bos ldquoEpac defining a newmechanism forcAMP actionrdquo Annual Review of Pharmacology and Toxicologyvol 50 pp 355ndash375 2010

[82] S Asuri J Yan N C Paranavitana and L A Quilliam ldquoE-cadherin dis-engagement activates the Rap1 GTPaserdquo Journalof Cellular Biochemistry vol 105 no 4 pp 1027ndash1037 2008

[83] G F Guidetti D Manganaro A Consonni I CanobbioC Balduini and M Torti ldquoPhosphorylation of the guanine-nucleotide-exchange factor CalDAG-GEFI by protein kinaseA regulates Ca(2+)-dependent activation of platelet Rap1bGTPaserdquo Biochemical Journal vol 453 no 1 pp 115ndash123 2013

[84] G Berruti ldquocAMP activates Rap1 in differentiating mousemale germ cells a new signaling pathway mediated by thecAMP-activated exchange factor Epacrdquo Cellular andMolecularBiology vol 49 no 3 pp 381ndash388 2003

[85] T Yamada T Sakisaka S Hisata T Baba and Y Takai ldquoRA-RhoGAP Rap-activated Rho GTPase-activating protein impli-cated in neurite outgrowth through Rhordquo Journal of BiologicalChemistry vol 280 no 38 pp 33026ndash33034 2005

[86] M Y Moon H J Kim J G Kim J Y Lee J Kim et alldquoSmall GTPase Rap1 regulates cellmigration through regulationof small GTPase RhoA activity in response to transforminggrowth factor-1205731rdquo Journal of Cellular Physiology vol 228 no11 pp 2119ndash2126 2013

[87] K J Teerds and J H Dorrington ldquoLocalization of transforminggrowth factor 1205731 and 1205732 during testicular development in theratrdquo Biology of Reproduction vol 48 no 1 pp 40ndash45 1993

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


aESaES

BTB

SpermiationaES

disassembly

Round spermatid


Elongated spermatid

Mature sperm

Sertoli cell

Sertoli cell

Pachytenespermatocyte

Basa

l com

part

men

tAd

lum

inal

com

part

men

t

Preleptotenespermatocyte

Apical ectoplasmic specialization

Basal ectoplasmic specialization

Tight junctionGap junctionDesmosome-like junction

Disassembled apical ES

Spermatogonium

Figure 1 A schematic drawing showing the junctions between Sertoli-Sertoli cells and Sertoli-germ cells as discussed in the review Thedrawing illustrates two Sertoli cells embracing germ cells at different stages of differentiation The Sertoli-Sertoli cell contacts namely tightjunction gap junction basal ectoplasmic specialization and desmosome-like junction give rise altogether to the blood-testis barrier (BTB)The BTB divides the seminiferous epithelium into basal and adluminal compartments In this last the apical ectoplasmic specialization (aEs)is established aEs is the unique type of anchoring junction between Sertoli cell and elongatingelongated spermatids It undergoes cycles ofassemblingdisassembling At spermiation it disassembles definitely to allow sperm release

contribute to create the blood-testis barrier (BTB) The BTBphysically divides the seminiferous epithelium in two com-partments that is a basal compartmentwhere spermatogoniaand spermatocytes reside and an adluminal compartmentwhere spermatids differentiate to develop into spermatozoa(Figure 1) [16 17] The establishment of the BTB is funda-mental for a successful spermatogenesis its integrity has tobemaintained throughout the entire spermatogenesis [18 19]The BTB provides in fact an immunological barrier to thedeveloping male germ cells it sequesters postmeiotic germcells from the systemic circulation thus preventing the pro-duction by the host of antibodies against spermatid-specificantigens whose expression is restricted to spermiogenesisonly [20] The BTB likely functions also as a gatekeeperenabling only the passage through the seminiferous epithe-lium of selected substancesmolecules of support to germcells The molecular components and the functions of the

BTB have been extensively reviewed (for excellent reviewssee [12 17 21]) it will be no longer discussed here

Conversely this brief review will focus around the apicalES (aES) restricted to Sertoli-postmeiotic germ cells at theadluminal compartment Differently from bES aES does notcoexist with other junctions the aES is the only junctionaldevice that sustains the association between Sertoli and elon-gatingelongated spermatids (from step 8 of differentiation)until the early phase of spermiation when it disassembles(Figure 1) [13 22ndash24]

2 Apical Ectoplasmic Specialization

The aES is the best known anchoring junction in the testisSeveral studies have led to a significant improvement of ourknowledge about its molecular architecture and molecular











VE-cadherin

Nectin-2

Nectin-3

Jam-C

p120-catenin

aPKC

Afadin

Par6Par3

Cdc42Sertoli cell

Afadin

Actin

fila

men

t

Jam-B


aEs stabiliz

ation

aES assembly

Cell polarization

120572-c

aten

in

120573-catenin








cAMP

Epac

Rap1

Cdc42

cAMP

Epac

Rap1

RA-RhoGAPRA-RhoGAP

Cdc42


Sertoli cell

Rap1 activation

Rho

Rap1 inactivation

Rho

Rap1-GAP




Afad

in

Afa

din

Nectin

-3 Par

com

plex

Jam-C

Actin

Actin

p120












6 Conclusion




References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























VE-cadherin

Nectin-2

Nectin-3

Jam-C

p120-catenin

aPKC

Afadin

Par6Par3

Cdc42Sertoli cell

Afadin

Actin

fila

men

t

Jam-B


aEs stabiliz

ation

aES assembly

Cell polarization

120572-c

aten

in

120573-catenin








cAMP

Epac

Rap1

Cdc42

cAMP

Epac

Rap1

RA-RhoGAPRA-RhoGAP

Cdc42


Sertoli cell

Rap1 activation

Rho

Rap1 inactivation

Rho

Rap1-GAP




Afad

in

Afa

din

Nectin

-3 Par

com

plex

Jam-C

Actin

Actin

p120












6 Conclusion




References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















cAMP

Epac

Rap1

Cdc42

cAMP

Epac

Rap1

RA-RhoGAPRA-RhoGAP

Cdc42


Sertoli cell

Rap1 activation

Rho

Rap1 inactivation

Rho

Rap1-GAP




Afad

in

Afa

din

Nectin

-3 Par

com

plex

Jam-C

Actin

Actin

p120












6 Conclusion




References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















6 Conclusion




References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article the dynamic of the apical ectoplasmic...

Documents