E XP ER I ME NTAL C E LL RE S E ARCH

] (]]]]) ]]]–]]]

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/yexcr

Review Article

Insight into planar cell polarity Michael Sebbagha,b,c,d,n, Jean-Paul Borga,b,c,d,n a

CRCM, “Equipe labellisée Ligue Contre le Cancer”, Inserm, U1068, Marseille F-13009, France Institut Paoli-Calmettes, Marseille F-13009, France c CNRS, UMR7258, Marseille F-13009, France d Aix-Marseille University, F-13284 Marseille, France b

article information

abstract

Article Chronology:

Planar cell polarity or PCP refers to a uniform cellular organization within the plan, typically

Received 11 May 2014

orthogonal to the apico-basal polarity axis. As such, PCP provides directional cues that control

Received in revised form

and coordinate the integration of cells in tissues to build a living organism. Although dysfunctions

30 August 2014

of this fundamental cellular process have been convincingly linked to the etiology of various

Accepted 1 September 2014

pathologies such as cancer and developmental defects, the molecular mechanisms governing its establishment and maintenance remain poorly understood. Here, we review some aspects of

Keywords: Planar cell polarity Wnt signaling

invertebrate and vertebrate PCPs, highlighting similarities and differences, and discuss the prevalence of the non-canonical Wnt signaling as a central PCP pathway, as well as recent findings on the importance of cell contractility and cilia as promising avenues of investigation.

Cilium

& 2014 Elsevier Inc. All rights reserved.

Contratility Diseases

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lessons from drosophila . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Similarities and differences with vertebrate PCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vertebrate core PCP members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vertebrate PCP core protein localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PCP and Wnt signaling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Downstream signaling pathways of PCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PCP and Human pathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 2 2 5 7 7 8

Abbreviations: AB, apico-basal polarity; AML, acute myeloid leukemia; CE, convergence extension; CLL, chronic lymphocytic leukemia; COPII, coat protein complex II; dpc, days post coïtum; Dvl, disheveled; ER, endoplasmic reticulum; Fz, frizzled receptor; JNK, jun kinase; MEF, mouse embryonic fibroblast; PAPC, paraxial protocadherin; PCP, planar cell polarity; TGN, trans-golgi-network

n Corresponding authors at: CRCM, UMR 1068, Institut Paoli-Calmettes, 27 bd Leï Roure BP 30059, 13273 Marseille cedex 09, France. Fax: þ33 4 86 97 74 99. E-mail addresses: [email protected] (M. Sebbagh), [email protected] (J.-P. Borg).

http://dx.doi.org/10.1016/j.yexcr.2014.09.005 0014-4827/& 2014 Elsevier Inc. All rights reserved.

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

2

E XP E RI ME N TAL CE L L R ES E ARC H

] (]]]]) ]]]–]]]

Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Introduction Most of the cells of multicellular organisms are polarized. The best described cell polarity process is apico-basal (AB) polarity, which characterizes epithelial and endothelial cells, and is discussed by others in this series of reviews. Nevertheless, the most widespread, and paradoxically the less well characterized form of polarity is planar cell polarity (PCP). Typically orthogonal to the AB polarity axis, PCP refers to a uniform cellular organization within the plan. Thus, PCP provides directional cues that control and coordinate the integration of cells in a tissue. As such, PCP is essential for multicellularization as it establishes a mutually coordinated planar polarization between contacting cells [1]. Although it is anticipated that PCP has to be established and maintained throughout the life cycle of an organism, its contribution is most obvious – and therefore most investigated – during the process of embryonic development, during which dynamic cellular rearrangements and tissue formation occur [1]. PCP is less studied in adult animals in normal conditions even though its role in hair alignment was demonstrated in adult mice [2]. Developmental studies in lower vertebrates (Xenopus laevis, Danio rerio) and in mice have revealed a potential contribution of PCP at the morula and blastocyst stages [3], but the most prominent aspects are observed at the gastrulation stage during the patterning of the proximal–distal and antero–posterior axis, and at later stages of development. During the embryonic development of vertebrates, alterations of PCP lead to typical and dramatic phenotypes used as read-outs of its dysfunctions, such as defects of embryonic left-right patterning [4,5], convergent extension (CE) [6] and associated neural tube closure, misorientation of hair bundles in inner ear sensory cells [7–9] and defects of organogenesis [10–12]. Even though a direct link between PCP and human diseases is more difficult to establish, the contribution of alterations of this developmental process to the etiology of cystic kidney diseases [13] and cancer [14–17] has now been well established. In those cases, it is believed that loss of PCP perturbs tissue organization and dynamic cellular processes, leading to uncontrolled migration or division of cells or group of cells [18–20]. Whereas the importance of PCP in normal physiology and diseases leaves no doubt, and that a growing number of PCP genes have been identified over the last 20 years, little is known about the molecular mechanisms governing PCP initiation and maintenance. Here, we have chosen to summarize the accumulated knowledge about the mechanisms of mammalian PCP and to discuss some of their most intriguing aspects.

Lessons from drosophila Genetic studies in invertebrates, especially in Drosophila melanogaster, have allowed the initial characterization of PCP and the identification of three sets of genes involved in this process recently reviewed by Axelrod and col. [21]. The so called “core PCP”, a highly evolutionary conserved module, comprises a set of genes required to prime the establishment of PCP, as demonstrated by the inactivation of these genes in Drosophila and vertebrates (Table 1). The encoded core PCP proteins belong to various protein families, from ligands (Wnts) to receptors (Celsr1, Frizzled, Vangl, Fat) and intracellular

proteins (Disheveled, Scrib, Prickle). These proteins are asymmetrically localized within and between cells forming an epithelial sheet. For example, in the Drosophila wing, whereas the atypical cadherin Flamingo (Celsr1 in vertebrates) is localized both at the distal and proximal sides of cells, the other core PCP members are each localized at either one side or the other (Fig. 1). Indeed, Van Gogh (also known as Strabismus in Drosophila, or Vangl in vertebrates) and Prickle accumulate at the distal side of the cell [22]; in contrast Frizzled (Fz) [23], Diego (Inversin) [24] and Disheveled (Dvl) [25] segregate at the proximal side. Such an asymmetric localization of core PCP proteins is considered sufficient to initiate a local cellular spatial organization through cell–cell contacts [22,26,27]. Propagation of this local organization through the tissue appears to be dependent on a second set of genes known as the “global module” [28–30]. In Drosophila, this module includes Four-jointed, a Golgi ectokinase, and two atypical cadherins: Fat and Daschous. Orientation cues propagated by these molecules are not based on their asymmetric cellular localization but rather on the modulated affinity between Fat and Daschous. Indeed, Fat and Daschous form heterodimers regulated by Four-jointed through phosphorylation [31,32]. Under the action of a currently undefined morphogenic gradient, Daschous and Four-jointed are expressed in opposing gradients throughout the tissue [33]. This would convert tissue-wide expression gradients into subcellular gradients of Fat within each cell [28,33]. The third and last set of PCP components includes genes responsible for the translation of the orientation cues into cellular polarized outputs that vary according to one specific tissue. Obviously, proteins involved in cytoskeletal organization are well represented in this set of PCP proteins, especially those affecting the contractile actin meshwork such as Rho1 and Drok (respectively RhoA and Rock in vertebrates) [34–38]. In Drosophila, the hierarchy between these different sets of genes remains unclear [1,21,39,40]. Recent work suggests that, in the wing, the establishment of PCP mainly results from the propagation of the plane of orientation of cell division from a few initial organized cells [41,42]. Interestingly, in these studies, it has been proposed that contraction at the wing hinge leads to an anisotropic tension along the proximal–distal axis [41], which might provide orientation cues contributing to core PCP asymmetrical localization as well as to establish the orientation of the cell division axis [42]. Indeed, these orientation cues overlap with the global module function governed by Fat–Daschous signaling, which regulates nuclear shuttling of the transcriptional factor Yorkie [43,44]. Interestingly, YAP, the vertebrate homolog of Yorkie, was shown to have an acto-myosin contractility-sensitive nuclear localization driven by external mechanical forces [45,46]. Although this mechanism is conserved in Drosophila [47], its potential contribution to PCP directional cues has to be clarified.

Similarities and differences with vertebrate PCP Vertebrate core PCP members In vertebrates, information on PCP has mainly been gathered from studies focusing on embryonic development, a period during

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

Core PCP members

PCP phenotypes

Vertebrate orthologue and paralogues

Localization

PCP phenotypes

Diego

þ

Disheveled

þ

Inversin Diversin DVL1–3

Centrosome and cilia Centrosome Membrane and centrosome

Cystic kidney, Heterotaxia Cystic kidney, Heterotaxia Cranorachischisis, stereocilia

Flamingo

þ

Celsr1–3

Asymetrically membrane

Frizzled Prickle

þ þ

Frizzled3&6 Prickle1–3

Asymetrically membrane and cilia Membrane ? and centrosome

Van gogh

þ

Vangl1–2

OTK Scribble

 

PTK7 Scrib

Asymetrically membrane and centrosme Membrane Membrane and centrosomen

Cranorachischisis, stereocilia, Hydrocephaly Cranorachischisis, stereocilia Epiblast; Palte cleft, skeleton and limb Cranorachischisis, stereocilia Left—right patterning Cranorachischisis, stereocilia Cranorachischisis, stereocilia

Sec24b Four-joint Daschous Fat

 þ þ þ

Sec24b Fjx1 Dash 1&2 Fat 1–4

Endoplasmic reticulum ? Membrane and centrosome Membrane and centrosome

Cranorachischisis, stereocilia None Cystic kidney, stereocilia Cystic kidney, stereocilia Cystic kidney, stereocilia, exencephaly None

Remarks

DVL2 & 3 KO DVL2 & 1 KO DVL1 & 3 Celsr1 Celsr2&3 Fz3 & 6 KO Prickle1 KO Vangl2 KO Vangl1&2 KO nCentrosomal by Mass Spectrometry

References

[4] [50,78,79] [51] [51] [51] [7,124] [83] [98] [3,65,66] [9] [49] [8] [59]

Fat4 KO Fat4 & 1 KO

[20,58] [48,57] [56] [55] [48]

Fat4 & 3 KO

[48]

] (]]]]) ]]]–]]]

Global module

Drosophila gene

E X PE R IM EN TA L C ELL R E S EA RC H

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

Table 1 – Invertebrates and vertebrates PCP proteins described in this review.

3

4

E XP E RI ME N TAL CE L L R ES E ARC H

] (]]]]) ]]]–]]]

Fig. 1 – Asymmetric localization of PCP core proteins at the adherens junctions of Drosophila epithelial cells.

which PCP defects lead to alteration of convergence extension and neural tube closure, and from studies on hair-bundle orientation of sensory cells in the inner ear. Unexpectedly, these studies have demonstrated rather limited similarities with the PCP scheme defined in the fly for several reasons. First, although all Drosophila PCP proteins are conserved, the presence of multiple vertebrate paralogs, which have specific spatiotemporal expression pattern in tissues or cell types, and which often exhibit functional redundancies, has complicated their characterization. Indeed, mammalian cells express four Fat [48] (Fat 1–4), two Daschous (Dash 1–2), two Van gogh [49] (Vangl 1–2), two Diego [4,50] (Inversin, Diversin), three Prickle (Pk 1–3), three Disheveled (Dvl 1–3 ) [51], three Flamingo (Celsr 1–3) [52] and ten Frizzled proteins [53] (Fz 1–10). Redundancy or partial compensation between paralogs is rather frequent, leading to the need to inactivate several paralogs in combination in order to reveal their function, as it was done for Vangl [49], Dvl [51] or Frizzled [54]. However, genetic interaction between paralogs can be even more complex as illustrated by the phenotypes observed in the Fat family. Indeed, whereas Fat4 knock-out mice display rather late developmental PCP defects (mainly misoriented cochlear stereocilia and cystic kidneys) [55], double Fat4/Fat1 knock-out mice present a more dramatic phenotype including early developmental defects such as exencephaly [48], suggesting some degree of compensation between these two Fat paralogs. However, in double Fat4/Fat3 knock-out mice, Fat3 deficiency antagonizes Fat4-dependent phenotypes in the kidney and the cochlea, suggesting that the Fat4 phenotype could be consecutive to an inappropriate Fat3 signaling [48]. Second, the relative functional importance of some PCP components has somehow changed over the course of evolution. For instance, whereas the Fat–Daschous cooperation is conserved between Drosophila and vertebrates [48,56], it is no longer regulated by the mammalian four-jointed homolog Fjx1 [48,57],

suggesting a different mode of regulation of the Fat–Daschous complex. Moreover, characterization of mutant mice presenting the most severe neural tube defect (cranioraschischisis) led to the discovery of new genes, i.e. PTK7 [8], Sec24b [20,58] and Scrib [20,59], which are not considered as core PCP members in Drosophila. Cranioraschischisis is also obtained following inactivation of Vangl2, a core PCP gene [9]. Likewise, PTK7, Scrib, and Sec24b were shown to genetically interact with Vangl2, suggesting their implication in a similar signaling PCP pathway, and were classified as core PCP genes in mammals [8,9,20,58,59]. For Scrib and Vangl2, the genetic interaction was translated into a physical interaction. Indeed, we and others have demonstrated that the Vangl2 C-terminal sequence directly binds to the Scrib PDZ 3 and 4 domains [60,61]. Other PDZ interactions have been described with the very same sequence of Vangl2 suggesting competition between the partners and/or spatio-temporal regulations [60,62]. Finally, the genetic background has a strong influence on the penetrance of the mouse phenotypes [63], which makes the analysis, comparison and interpretation of the various developmental studies more complicated. For instance, mouse Prickle1 inactivation causes an early developmental arrest between E5.5 and E6.5 dpc (day post coïtum), at the end of gastrulation at the stage of epiblast formation [3]. Other reports suggest less severe and later developmental phenotypes (around E13 dpc) which include skeletal [64], convergence extension [65] and palate closure [66] defects. Similar abnormalities have been associated with rare Prickle1 mutations in human disorders [64–66]. Overall, although it appears that all Drosophila PCP genes are phylogenetically conserved in mammals, the function of some of them has significantly evolved away from their initial roles in PCP. This is especially the case for genes of the global module (i.e. Fat, Four-joint and Daschous) albeit keeping a significant influence on mammalian PCP establishment [48,56,57]. In parallel, the number of core mammalian PCP module genes has grown in evolution

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

E X PE R IM EN TA L C ELL R E S EA RC H

with the addition of PTK7, Sec24b and Scrib. Of note, the diptera homolog of Scrib (Scribble) has been mainly involved in AB polarity [67,68], but its role as a PCP effector was proposed by Courbard et al. [69]. PTK7 (Otk in Drosophila) and Sec24b have not been described to be involved in PCP in the fly yet.

Vertebrate PCP core protein localization By definition and as illustrated in Drosophila studies, cell polarity relies on the asymmetrical localization and dynamic of PCP components. As is the case in Drosophila, Vangl2 has been shown to be asymmetrically localized at the plasma membrane along the antero–posterior axis, especially in the mouse cochlea and epidermis [2,61]. These studies demonstrate that Vangl2 localization correlates with that of Celsr1 and is functionally required to asymmetrically localize Frizzled-6. The mechanism governing the trafficking and asymmetric localization of Vangl2 is in the process of being elucidated. Mutant mice deficient for Vangl2 and Sec24b present similar PCP phenotypes and a genetic interaction is shown between these two PCP members. Of interest, Vangl2, but not PTK7, localization was shown to be dependent on Sec24b, demonstrating a strict specificity in the PCP pathway [20,58]. Sec24b is a component of the coat protein complex II (COPII) and is essential for endoplasmic reticulum (ER)-to-Golgi protein

] (]]]]) ]]]–]]]

5

transport [70]. As expected, Sec24b is responsible for the trafficking of Vangl2 between these two cellular compartments [20,58]. Exit of Vangl2 from the Trans-Golgi-network (TGN) has been described to be dependent on AP1, which is itself directed to the plasma membrane by the Arfrp1 GTPase [71] (Fig. 2). PTK7 seems to follow the same TGN exit pathway, whereas localization of Celsr1 and Frizzled-6 is not sensitive to Arfrp1 inhibition [71]. Interestingly, Vangl2 and PTK7 localizations at the plasma membrane also requires Rack1 (Receptor of activated protein kinase C1), a common partner of these two PCP proteins [72,73]. Thus, subtle similarities and differences exist among PCP members in the mode of trafficking. The mechanism of removal of Vangl2 from the membrane that may contribute to the asymmetric distribution of the protein is still unclear but we have recently described possible actors of this event. Through a two hybrid screen using the Vangl2 C-terminal PDZ binding motif as a bait, we isolated GIPC and SNX27 as Vangl2 partners [60]. It was previously described that the very same Vangl2 sequence directly interacted with the GIPC PDZ domain, and that GIPC, in association with Myosin VI, contributed to Vangl2 membrane's removal [62]. The novel Vangl2–SNX27 interaction could be involved in this process or in Vangl2 recycling as well, since SNX27 belongs to the retromer complex, the cellular machinery driving recycling. The retromer and SNX27 could have an even more generic

Fig. 2 – Overview of the localization and traffic of vertebrate PCP members described in this review. Yellow arrows indicate direction of trafficking and proteins involved in the routing are mentioned on each arrow. TGN for Trans-Golgi Network. ER for Endoplasmic Reticulum. Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

6

E XP E RI ME N TAL CE L L R ES E ARC H

implication on membrane removal or recycling of core PCP members, as Steinberg et al. [74] have identified Celsr1, Celsr2, Fat1, Fat4, PTK7 and Frizzled-6 as retromer targets. Another specificity of vertebrate core PCP members is relative to their localization in discrete subcellular compartments. Indeed, some PCP components are not only present at the plasma membrane, but also at the cilium or at the centrosome (or basal body), at the base of the cilium. Cilia are membrane-bound, centriole-derived, microtubule-containing projections protruding at the surface of almost all vertebrate cells but absent in Drosophila [75,76]. Some cells can develop up to hundreds of – usually motile – cilia at their surface, which contribute to generate a fluid flow within the cerebrospinal media or lung mucus [76]. However most cells bear a single non-motile cilium, called the primary cilium [75,76]. The Diego homolog, Inversin, mainly localizes to this organelle [4,77] whereas its paralog Diversin primarily locates at its base [50,78,79], like other PCP proteins such as Disheveled (Dvl) [80], Fat4 [48], Daschous [48], Prickle [81], potentially Vangl2 [82], and Scrib [81]. The functional importance of this localization was confirmed, as Celsr2 and 3 inactivation impairs the formation of motile cilia on ependymal cells, leading to altered cerebrospinal flow and fatal hydrocephalus [83]. In this case, loss of Celsr is associated to mislocalization

] (]]]]) ]]]–]]]

of Vangl2, the inactivation of which leads to a similar phenotype not by impeding ciliogenesis but by interfering with the proper alignment and localization of the cilium [84]. The involvement of PCP proteins in the alignment of motile cilium was also highlighted when Diversin was inactivated [78,79]. Another example of the implication of PCP directional cues in the initial symmetry breaking event is embryonic Left–Right (L–R) patterning. L–R patterning is due to a leftward flow of liquid at a transient structure called the embryonic node. Nodal flow is driven by cilia rotation [85,86]. Misalignment or mislocalization of motile cilia generates an altered and inefficient flow, leading to random L–R patterning and to some forms of heterotaxia such as situs inversus [85,87]. This phenotype was also observed in Vangl2 deficient mice, only in the context of a simultaneous Vangl1 deficiency [49], reflecting a functional compensation between the two homologs that can form homo and heterodimers [88]. The mechanisms involved in cilia alignment and localization remain unclear. However, genetic studies have highlighted the importance of a cofilin-dependent actin remodeling process able to localize Vangl2 and Celsr1 [89]. In the same way, the ciliary Bardet–Bield syndrome proteins 4 [82] and 8 [90] as well as Bbof1 [91] genetically interact with Vangl2 and are required for cilia formation and alignment. Moreover, studies on the localization and

Fig. 3 – Overview of the canonical (yellow) or non-canonical (blue) Wnt pathways. Arrows for activation, stop line for inhibition. U and P in yellow circle for ubiquitination and phosphorylation, respectively. Green dashed proteins for proteasomal degradation. Black arrows for effect on localization. Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

E X PE R IM EN TA L C ELL R E S EA RC H

orientation of the kinocilium, a specialized cilia in the cochlea of the inner ear, have partially revealed the molecular mechanism by demonstrating that kinocilium localization involved mlnsc, LGN and Gαi proteins, which classically regulate mitotic spindle orientation [92,93]. Identification of protein complexes regulating spindle orientation and cilia positioning might also contribute to a better understanding of other PCP related defects. Indeed, the role of core PCP members is not restricted to the alignment of motile cilia; they also play a role in primary cilia functions, which is less well characterized. Indeed, kidney development or pathologies such as polycytic kidney disease resulting from a disabled primary cilium unable to sense flow can be caused by mutations in the PKD1 or PKD2 genes [13,94]. These mutations lead to cyst formation mainly through alterations of the mitotic spindle orientation. The fact that inactivation of PCP genes such as vangl2 [10], inversin [4,95] or fat1 and fat4 [48,55] results in similar alterations may be due to an impact of these PCP genes on mitotic spindle protein complex regulation. On the other hand, the impairment of ciliogenesis by IFT88 or KIF3b inactivation does not impede certain PCP processes such as convergence extension [75] but leads to defects of cochlea stereocilia orientation [96]. It thus seems that the cilium axoneme is dispensable for some PCP functions. In conclusion, whereas the link between PCP and cilia has been well established by recent reports, the nature of their relationship remains unclear and future studies will have to address whether PCP signaling is lying upstream or downstream cilium positioning and function [75,76,96].

PCP and Wnt signaling pathways Currently, vertebrate PCP is considered to be governed by Frizzled (Fz) receptors through their stimulation by Wnt ligands. In mammals, 10 Fz and 19 Wnt genes have been identified [53]. Wnt signaling is split into two branches defined as the noncanonical and the canonical pathways, the latter leading to β-catenin stabilization, nuclear accumulation and transcriptional activation in conjunction with TCF/LEF factors [53]. Some of the non-canonical Fz receptors and Wnt ligands have been described as PCP components. Indeed, Wnt5a contributes to CE processes [97], while Fz3 and Fz6 inactivation in the mouse leads to craniorachischisis [98]. This dramatic defect is phenocopied by the loss of core PCP members such as Vangl2, Scrib, Sec24b, Celsr1 and PTK7. All these PCP components have been directly (PTK7, see below) or indirectly linked to Wnt signaling. Indeed, Sec24b, Celsr1-3, Vangl2 and Scrib are required for the proper localization of Fz [61,83]. These observations and others recently summarized by Gao [99] have led to consider PCP as a non-canonical Wnt process, often referred to as the Wnt/PCP pathway. However, the picture is far more complex as shown in Fig. 3. Indeed, the canonical and non-canonical Wnt signaling pathways crosstalk and antagonize each other [99]. Moreover, some PCP components such as PTK7 and Ryk have dual roles in Wnt signaling. Indeed, PTK7 can positively regulate canonical Wnt signaling during Xenopus development, including through a direct interaction with β-catenin [100–102]. Depending on the context, PTK7 is also able to negatively regulate canonical Wnt signaling [103] thus favoring the non-canonical pathway. Ryk, like PTK7, is a transmembrane receptor harboring a non-functional kinase domain that can positively modulate canonical [104] or non-canonical

] (]]]]) ]]]–]]]

7

Wnt [105] signaling depending on the type of model considered. Moreover, the contribution of the primary cilium to the regulation of canonical Wnt signaling [106] is also a bridge between PCP and Wnt dependent processes. Indeed, two core PCP proteins Inversin and Diversin which localize at the primary cilium are considered to fulfill their function mainly by modulating the Wnt pathways. Inversin was shown to favor proteasomal degradation of Dvl1, thus impairing β-catenin stabilization and canonical Wnt activation [95]. Diversin physically associates with Axin and Casein kinase, two critical compounds of the β-catenin degradation complex. Indeed, Casein kinase I (CKI) phosphorylates β-catenin at critical sites leading to proteasomal degradation. Diversin would thus contribute to β-catenin degradation and canonical Wnt pathway inhibition by allowing the spatial proximity between β-catenin and CKI [50,107]. Finally, Wnt signaling is also linked to PCP through the Fat–Daschous signaling [108,109]. Indeed, shuttling of YAP and TAZ between the cytosol and the nucleus is driven by Fat signaling and also contributes to β-catenin stabilization [108] and nucleus translocation [108–110]. Overall, these data show that PCP members play a role in canonical Wnt signaling and that restricting their role to the non-canonical Wnt signaling is probably an oversimplification.

Downstream signaling pathways of PCP PCP downstream signals are still poorly defined. One of the first pathway to be identified was the Jun Kinase (JNK) pathway. In Xenopus, it was shown that the non-canonical Wnt5a ligand governs CE in part through JNK activation [111]. JNK phosphorylates and activates transcriptional factor such as ATF2 (Fig. 3), which is commonly used in reporter gene assays to reveal noncanonical Wnt signaling [112]. JNK activity was for instance shown to play a crucial role in the regulation of the expression of PAPC [113], a protocadherin involved in morphogenetic movements during Xenopus gastrulation. However, PCP-associated JNK activation and function are difficult to decipher as JNK is also commonly involved in cellular stress responses. In PCP, JNK activation is closely linked to the activation of a family of small monomeric Rho GTPases that comprises RhoA, Rac and Cdc42. RhoA has a broad role, not restricted to PCP, especially in cellular signaling through its effects on actin cytoskeleton remodeling [114]. Like other Rho GTPases of the family (Rac and Cdc42), RhoA regulates the actin cytoskeleton in a number of ways, for instance through actin stabilization or by promoting actin polymerization and activation of the mammalian Diaphanous-related formin (mDia) [114]. In addition, RhoA activity governs cell contractility which has a central role in PCP [115]. Indeed, tissue remodeling during development [115,116] or cell/tissue shape regulation [115,117], cell division [118,119] and migration, primary cilium positioning [120] and stereocilia orientation [121] are all PCPrelated processes dependent on Actin–Myosin II contractility and a RhoA-Rock1/Rock2 cascade [114,115]. Cell contractility could be therefore the common downstream effect of PCP signaling (Fig. 4). A recent report shows that misorientation of stereocilia in cochlea of PTK7 deficient mice is correlated with reduced cell contractility [121]. The authors suggest that PTK7 spatially regulates cell contractility by modulating Rock2 activity through the recruitment and activation of the Src tyrosine kinase [122]. Reduced cell contractility, especially at the apical domain of neural plate cell,

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

8

E XP E RI ME N TAL CE L L R ES E ARC H

] (]]]]) ]]]–]]]

Fig. 4 – Scheme of the neural plate before closure (bottom, right). In red, Acto–Myosin II complex contractility as defined by [123] at the apical domain or by [116,122] at the lateral domain. Detailed views of the contents of black boxes describe the molecular mechanisms involved.

has also been associated with neural tube closure defects observed in either PTK7 or Vangl2 deficient mice [116]. A requirement for apical contractility during neural tube closure was first suggested by the lab of Takeichi and coworkers [123]. Apical contractility was shown to be dependent on Celsr1, a cell surface PCP molecule whose loss of function leads to Vangl2 and PTK7-like phenotypes [7,124]. Celsr1 recruits PDZ-RhoGEF to stimulate apical RhoA, which then recruits DAAM1, a Formin family member to polymerize actin at the apical domain, leading to Acto–Myosin II contractility. However, apical contractility during neural tube closure was also shown to be dependent on the localization of the PDZ domain protein Shroom3 by Lulu, a member of the FERM family [125]. The involvement of Shroom in restricting contractility at the basolateral domain has also been described in CE [126], suggesting conserved functions in multiple subcellular locations. Like PCP components, Septins can also spatially confine contractility in collective cell migration [127]. These examples underline the importance of spatially restricted cell contractility during PCP processes.

PCP and Human pathologies Evidence of PCP defects in human diseases is growing. Indeed, mutations in human core PCP members have been associated with developmental disorders such as cranorachischisis [124], spina bifida [6,128], palate cleft defects [66] or some forms of heterotaxia and cystic kidney diseases [4]. Some of these pathologies share features with primary cilia disorders called ciliopathies. For example, the Meckel–Gruber and Joubert syndromes are ciliopathies leading to polydactyly, situs inversus and cystic kidney as PCP disorders [129,130].

In epithelial tumors, studies have reported no mutations but rather aberrant levels of expression or mislocalization of PCP proteins such as PTK7 [101], Scrib [131,132], Vangl1 [14] or Diversin [15]. In such cases, PCP alterations have no obvious impact on tumor growth and are considered to primarily affect cell invasion [18,133], cell migration [19,60], and metastasis dissemination, facilitated by metalloproteinase shedding [18,133]. Alterations of PCP protein expression were also found in non-epithelial neoplasia such as Chronic Lymphocytic Leukemia [134] or Acute Myeloid Leukemia [17], again correlating with increased cell dissemination and resistance to chemotherapy. In these examples, PCP alterations occur in tumoral cells and promote tumor dissemination in a cell-autonomous manner. A recent report sheds light on a novel prometastatic and non-cell autonomous process involving activation of PCP. In a model of MDA-MB231 breast cell carcinoma, fibroblasts from the tumor microenvironment secreting exosomes can package growth factors including Wnt ligands in target tumoral cells and promote tumor dissemination through PCP molecules such as Vangl1 and Prickle activated by an autocrine Wnt loop [135]. From this study, it seems worthwhile to further investigate whether altered PCP signaling may be due to the abnormal communication between microenvironment and tumoral cells.

Perspectives PCP is an important process required for embryonic development and involved in an increasing number of diseases. Our understanding of the mechanisms that tune its activity remains poor as compared to that of apico-basal polarity. Although PCP was initially defined as a process allowing cell coordination and tissue organization, the identification of PCP actors and their

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

E X PE R IM EN TA L C ELL R E S EA RC H

involvement in cellular functions, notably in cell migration, chemotaxis and axon guidance has led to a redefinition as a generic pathway required for cell organization within the plane. The possibility that the final outcome of PCP signaling is to spatially restrict cell contractility, as it was reported at the cell [136] and tissue [121,122] levels, should be further explored. The dissection of the links between PCP and cilium positioning and functions remains also an interesting avenue of research. At the molecular level, the mode of action of most PCP molecules is far from clear and efforts are needed to reveal the associated protein networks, draw the organization of the pathway and clarify the links with others.

Acknowledgments The authors would like to thank Dr. Marie-Josée Santoni for her scientific input over the course of our studies and for the preparation of this review, and apologize to researchers whose investigations were not included due to space limitation. We thank Dr. Valérie Ferrier for her implication in the writing of the manuscript. The JPB's lab is supported by INSERM, Institut PaoliCalmettes, La Ligue Nationale Contre le Cancer (“Equipe labellisée”), INCa (Project Libre INCa 2012-108) and SIRIC program (INCa-DGOS-Inserm 6038). MS is supported by ARC association (Projet Fondation ARC 2011). Jean-Paul Borg is a Scholar of Institut Universitaire de France.

references [1] L.V. Goodrich, D. Strutt, Principles of planar polarity in animal development, Development 138 (2011) 1877–1892. [2] D. Devenport, E. Fuchs, Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles, Nat. Cell Biol. 10 (2008) 1257–1268. [3] H. Tao, M. Suzuki, H. Kiyonari, T. Abe, T. Sasaoka, N. Ueno, Mouse prickle1, the homolog of a PCP gene, is essential for epiblast apical-basal polarity, Proc. Natl. Acad. Sci. U S A 106 (2009) 14426–14431. [4] E.A. Otto, B. Schermer, T. Obara, J.F. O’Toole, K.S. Hiller, A.M. Mueller, R.G. Ruf, J. Hoefele, F. Beekmann, D. Landau, J.W. Foreman, J.A. Goodship, T. Strachan, A. Kispert, M.T. Wolf, M.F. Gagnadoux, H. Nivet, C. Antignac, G. Walz, I.A. Drummond, T. Benzing, F. Hildebrandt, Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination, Nat. Genet. 34 (2003) 413–420. [5] Y. Zhang, M. Levin, Left-right asymmetry in the chick embryo requires core planar cell polarity protein Vangl 2, Genesis 47 (2009) 719–728. [6] Y.P. Lei, T. Zhang, H. Li, B.L. Wu, L. Jin, H.Y. Wang, VANGL2 mutations in human cranial neural-tube defects, N. Engl. J. Med. 362 (2010) 2232–2235. [7] J.A. Curtin, E. Quint, V. Tsipouri, R.M. Arkell, B. Cattanach, A.J. Copp, D.J. Henderson, N. Spurr, P. Stanier, E.M. Fisher, P.M. Nolan, K.P. Steel, S.D. Brown, I.C. Gray, J.N. Murdoch, Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse, Curr. Biol. 13 (2003) 1129–1133. [8] X. Lu, A.G. Borchers, C. Jolicoeur, H. Rayburn, J.C. Baker, M. Tessier-Lavigne, PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates, Nature 430 (2004) 93–98. [9] M. Montcouquiol, R.A. Rachel, P.J. Lanford, N.G. Copeland, N.A. Jenkins, M.W. Kelley, Identification of Vangl2 and Scrb1 as planar polarity genes in mammals, Nature 423 (2003) 173–177.

] (]]]]) ]]]–]]]

9

[10] L.L. Yates, J. Papakrivopoulou, D.A. Long, P. Goggolidou, J.O. Connolly, A.S. Woolf, C.H. Dean, The planar cell polarity gene Vangl2 is required for mammalian kidney-branching morphogenesis and glomerular maturation, Hum. Mol. Genet. 19 (2010) 4663–4676. [11] L.L. Yates, C. Schnatwinkel, J.N. Murdoch, D. Bogani, C.J. Formstone, S. Townsend, A. Greenfield, L.A. Niswander, C.H. Dean, The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis, Hum. Mol. Genet. 19 (2010) 2251–2267. [12] D.J. Henderson, S.J. Conway, N.D. Greene, D. Gerrelli, J.N. Murdoch, R.H. Anderson, A.J. Copp, Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant, Circ. Res. 89 (2001) 6–12. [13] E. Papakrivopoulou, C.H. Dean, A.J. Copp, D.A. Long, Planar cell polarity and the kidney, Nephrol. Dial. Transplant. (2013). [14] J.N. Anastas, T.L. Biechele, M. Robitaille, J. Muster, K.H. Allison, S. Angers, R.T. Moon, A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression, Oncogene 31 (2012) 3696–3708. [15] L. Luan, Y. Zhao, Z. Xu, G. Jiang, X. Zhang, C. Fan, D. Liu, H. Zhao, K. Xu, M. Wang, X. Yu, E. Wang, Diversin increases the proliferation and invasion ability of non-small-cell lung cancer cells via JNK pathway, Cancer Lett. 344 (2014) 232–238. [16] G. Piazzi, M. Selgrad, M. Garcia, C. Ceccarelli, L. Fini, P. Bianchi, L. Laghi, L. D’Angelo, P. Paterini, P. Malfertheiner, P. Chieco, C.R. Boland, F. Bazzoli, L. Ricciardiello, Van-Gogh-like 2 antagonises the canonical WNT pathway and is methylated in colorectal cancers, Br. J. Cancer 108 (2013) 1750–1756. [17] T. Prebet, A.C. Lhoumeau, C. Arnoulet, A. Aulas, S. Marchetto, S. Audebert, F. Puppo, C. Chabannon, D. Sainty, M.J. Santoni, M. Sebbagh, V. Summerour, Y. Huon, W.S. Shin, S.T. Lee, B. Esterni, N. Vey, J.P. Borg, The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome, Blood 116 (2010) 2315–2323. [18] V.A. Cantrell, J.R. Jessen, The planar cell polarity protein Van GoghLike 2 regulates tumor cell migration and matrix metalloproteinasedependent invasion, Cancer Lett. 287 (2010) 54–61. [19] S. Nola, M. Sebbagh, S. Marchetto, N. Osmani, C. Nourry, S. Audebert, C. Navarro, R. Rachel, M. Montcouquiol, N. Sans, S. Etienne-Manneville, J.P. Borg, M.J. Santoni, Scrib regulates PAK activity during the cell migration process, Hum. Mol. Genet. 17 (2008) 3552–3565. [20] C. Wansleeben, H. Feitsma, M. Montcouquiol, C. Kroon, E. Cuppen, F. Meijlink, Planar cell polarity defects and defective Vangl2 trafficking in mutants for the COPII gene Sec24b, Development 137 (2010) 1067–1073. [21] Y. Peng, J.D. Axelrod, Asymmetric protein localization in planar cell polarity: mechanisms, puzzles, and challenges, Curr. Top. Dev. Biol. 101 (2012) 33–53. [22] R. Bastock, H. Strutt, D. Strutt, Strabismus is asymmetrically localised and binds to Prickle and Disheveled during Drosophila planar polarity patterning, Development 130 (2003) 3007–3014. [23] D.I. Strutt, Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing, Mol. Cell 7 (2001) 367–375. [24] G. Das, A. Jenny, T.J. Klein, S. Eaton, M. Mlodzik, Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes, Development 131 (2004) 4467–4476. [25] J.D. Axelrod, Unipolar membrane association of Disheveled mediates Frizzled planar cell polarity signaling, Genes Dev. 15 (2001) 1182–1187. [26] W.S. Chen, D. Antic, M. Matis, C.Y. Logan, M. Povelones, G.A. Anderson, R. Nusse, J.D. Axelrod, Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling, Cell 133 (2008) 1093–1105. [27] H. Strutt, S.J. Warrington, D. Strutt, Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains, Dev. Cell 20 (2011) 511–525.

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

10

E XP E RI ME N TAL CE L L R ES E ARC H

[28] A.A. Ambegaonkar, G. Pan, M. Mani, Y. Feng, K.D. Irvine, Propagation of Dachsous-Fat planar cell polarity, Curr. Biol. 22 (2012) 1302–1308. [29] K. Amonlirdviman, N.A. Khare, D.R. Tree, W.S. Chen, J.D. Axelrod, C.J. Tomlin, Mathematical modeling of planar cell polarity to understand domineering nonautonomy, Science 307 (2005) 423–426. [30] D. Ma, C.H. Yang, H. McNeill, M.A. Simon, J.D. Axelrod, Fidelity in planar cell polarity signalling, Nature 421 (2003) 543–547. [31] A.L. Brittle, A. Repiso, J. Casal, P.A.. Lawrence, D. Strutt, Fourjointed modulates growth and planar polarity by reducing the affinity of dachsous for fat, Curr. Biol. 20 (2010) 803–810. [32] M.A. Simon, A. Xu, H.O. Ishikawa, K.D. Irvine, Modulation of fat: dachsous binding by the cadherin domain kinase four-jointed, Curr. Biol. 20 (2010) 811–817. [33] A. Brittle, C. Thomas, D. Strutt, Planar polarity specification through asymmetric subcellular localization of Fat and Dachsous, Curr. Biol. 22 (2012) 907–914. [34] P. Skoglund, A. Rolo, X. Chen, B.M. Gumbiner, R. Keller, Convergence and extension at gastrulation require a myosin IIBdependent cortical actin network, Development 135 (2008) 2435–2444. [35] D.I. Strutt, U. Weber, M. Mlodzik, The role of RhoA in tissue polarity and Frizzled signalling, Nature 387 (1997) 292–295. [36] K. Sugihara, N. Nakatsuji, K. Nakamura, K. Nakao, R. Hashimoto, H. Otani, H. Sakagami, H. Kondo, S. Nozawa, A. Aiba, M. Katsuki, Rac1 is required for the formation of three germ layers during gastrulation, Oncogene 17 (1998) 3427–3433. [37] L. Wei, W. Roberts, L. Wang, M. Yamada, S. Zhang, Z. Zhao, S.A. Rivkees, R.J. Schwartz, K. Imanaka-Yoshida, Rho kinases play an obligatory role in vertebrate embryonic organogenesis, Development 128 (2001) 2953–2962. [38] C.G. Winter, B. Wang, A. Ballew, A. Royou, R. Karess, J.D. Axelrod, L. Luo, Drosophila Rho-associated kinase (Drok) links Frizzledmediated planar cell polarity signaling to the actin cytoskeleton, Cell 105 (2001) 81–91. [39] P.N. Adler, The frizzled/stan pathway and planar cell polarity in the Drosophila wing, Curr. Top. Dev. Biol. 101 (2012) 1–31. [40] P.A. Lawrence, J. Casal, The mechanisms of planar cell polarity, growth and the Hippo pathway: some known unknowns, Dev. Biol. 377 (2013) 1–8. [41] B. Aigouy, R. Farhadifar, D.B. Staple, A. Sagner, J.C. Roper, F. Julicher, S. Eaton, Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila, Cell 142 (2010) 773–786. [42] A. Sagner, M. Merkel, B. Aigouy, J. Gaebel, M. Brankatschk, F. Julicher, S. Eaton, Establishment of global patterns of planar polarity during growth of the Drosophila wing epithelium, Curr. Biol. 22 (2012) 1296–1301. [43] J. Huang, S. Wu, J. Barrera, K. Matthews, D. Pan, The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP, Cell 122 (2005) 421–434. [44] H. Oh, K.D. Irvine, In vivo regulation of Yorkie phosphorylation and localization, Development 135 (2008) 1081–1088. [45] M. Aragona, T. Panciera, A. Manfrin, S. Giulitti, F. Michielin, N. Elvassore, S. Dupont, S. Piccolo, A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors, Cell 154 (2013) 1047–1059. [46] S. Dupont, L. Morsut, M. Aragona, E. Enzo, S. Giulitti, M. Cordenonsi, F. Zanconato, J. Le Digabel, M. Forcato, S. Bicciato, N. Elvassore, S. Piccolo, Role of YAP/TAZ in mechanotransduction, Nature 474 (2011) 179–183. [47] L. Sansores-Garcia, W. Bossuyt, K. Wada, S. Yonemura, C. Tao, H. Sasaki, G. Halder, Modulating F-actin organization induces organ growth by affecting the Hippo pathway, EMBO J. 30 (2011) 2325–2335. [48] S. Saburi, I. Hester, L. Goodrich, H. McNeill, Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity, Development 139 (2012) 1806–1820.

] (]]]]) ]]]–]]]

[49] H. Song, J. Hu, W. Chen, G. Elliott, P. Andre, B. Gao, Y. Yang, Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning, Nature 466 (2010) 378–382. [50] K. Itoh, A. Jenny, M. Mlodzik, S.Y. Sokol, Centrosomal localization of Diversin and its relevance to Wnt signaling, J. Cell Sci. 122 (2009) 3791–3798. [51] S.L. Etheridge, S. Ray, S. Li, N.S. Hamblet, N. Lijam, M. Tsang, J. Greer, N. Kardos, J. Wang, D.J. Sussman, P. Chen, A. WynshawBoris, Murine disheveled 3 functions in redundant pathways with disheveled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development, PLoS Genet. 4 (2008) e1000259. [52] C. Boutin, A.M. Goffinet, F. Tissir, Celsr1-3 cadherins in PCP and brain development, Curr. Top. Dev. Biol. 101 (2012) 161–183. [53] S. Angers, R.T. Moon, Proximal events in Wnt signal transduction, Nat. Rev. Mol. Cell Biol. 10 (2009) 468–477. [54] X. Ye, Y. Wang, A. Rattner, J. Nathans, Genetic mosaic analysis reveals a major role for frizzled 4 and frizzled 8 in controlling ureteric growth in the developing kidney, Development 138 (2011) 1161–1172. [55] S. Saburi, I. Hester, E. Fischer, M. Pontoglio, V. Eremina, M. Gessler, S.E. Quaggin, R. Harrison, R. Mount, H. McNeill, Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease, Nat. Genet. 40 (2008) 1010–1015. [56] Y. Mao, J. Mulvaney, S. Zakaria, T. Yu, K.M. Morgan, S. Allen, M.A. Basson, P. Francis-West, K.D. Irvine, Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development, Development 138 (2011) 947–957. [57] B. Probst, R. Rock, M. Gessler, A. Vortkamp, A.W. Puschel, The rodent Four-jointed ortholog Fjx1 regulates dendrite extension, Dev. Biol. 312 (2007) 461–470. [58] J. Merte, D. Jensen, K. Wright, S. Sarsfield, Y. Wang, R. Schekman, D.D. Ginty, Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure, Nat. Cell Biol. 12 (2010) 41–48 (41-46; sup). [59] J.N. Murdoch, D.J. Henderson, K. Doudney, C. Gaston-Massuet, H.M. Phillips, C. Paternotte, R. Arkell, P. Stanier, A.J. Copp, Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse, Hum. Mol. Genet. 12 (2003) 87–98. [60] E. Belotti, J. Polanowska, A.M. Daulat, S. Audebert, V. Thome, J.C. Lissitzky, F. Lembo, K. Blibek, S. Omi, N. Lenfant, A. Gangar, M. Montcouquiol, M.J. Santoni, M. Sebbagh, M. Aurrand-Lions, S. Angers, L. Kodjabachian, J. Reboul, J.P. Borg, The human PDZome: a gateway to PSD95-Disc large-zonula occludens (PDZ)-mediated functions, Mol. Cell. Proteomics 12 (2013) 2587–2603. [61] M. Montcouquiol, N. Sans, D. Huss, J. Kach, J.D. Dickman, A. Forge, R.A. Rachel, N.G. Copeland, N.A. Jenkins, D. Bogani, J. Murdoch, M.E. Warchol, R.J. Wenthold, M.W. Kelley, Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals, J. Neurosci. 26 (2006) 5265–5275. [62] A.P. Giese, J. Ezan, L. Wang, L. Lasvaux, F. Lembo, C. Mazzocco, E. Richard, J. Reboul, J.P. Borg, M.W. Kelley, N. Sans, J. Brigande, M. Montcouquiol, Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear, Development 139 (2012) 3775–3785. [63] M.A. Surani, Influence of genome imprinting on gene expression, phenotypic variations and development, Hum. Reprod. 6 (1991) 45–51. [64] T. Yang, A.G. Bassuk, B. Fritzsch, Prickle1 stunts limb growth through alteration of cell polarity and gene expression, Dev. Dyn. 242 (2013) 1293–1306. [65] C.M. Bosoi, V. Capra, R. Allache, V.Q. Trinh, P. De Marco, E. Merello, P. Drapeau, A.G. Bassuk, Z. Kibar, Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects, Hum. Mutat. 32 (2011) 1371–1375. [66] T. Yang, Z. Jia, W. Bryant-Pike, A. Chandrasekhar, J.C. Murray, B. Fritzsch, A.G. Bassuk, Analysis of PRICKLE1 in human cleft

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

E X PE R IM EN TA L C ELL R E S EA RC H

[67]

[68] [69]

[70] [71]

[72]

[73]

[74]

[75] [76] [77]

[78]

[79] [80]

[81]

[82]

[83]

[84]

palate and mouse development demonstrates rare and common variants involved in human malformations, Mol. Genet. Genomic Med. 2 (2014) 138–151. D. Bilder, N. Perrimon, Localization of apical epithelial determinants by the basolateral PDZ protein Scribble, Nature 403 (2000) 676–680. M.J. Santoni, P. Pontarotti, D. Birnbaum, J.P. Borg, The LAP family: a phylogenetic point of view, Trends Genet. 18 (2002) 494–497. J.R. Courbard, A. Djiane, J. Wu, M. Mlodzik, The apical/basalpolarity determinant Scribble cooperates with the PCP core factor Stbm/Vang and functions as one of its effectors, Dev. Biol. 333 (2009) 67–77. K. Sato, A. Nakano, Mechanisms of COPII vesicle formation and protein sorting, FEBS Lett. 581 (2007) 2076–2082. Y. Guo, G. Zanetti, R. Schekman, A novel GTP-binding proteinadaptor protein complex responsible for export of Vangl2 from the trans Golgi network, Elife 2 (2013) e00160. S. Li, R. Esterberg, V. Lachance, D. Ren, K. Radde-Gallwitz, F. Chi, J.L. Parent, A. Fritz, P. Chen, Rack1 is required for Vangl2 membrane localization and planar cell polarity signaling while attenuating canonical Wnt activity, Proc. Natl. Acad. Sci. USA 108 (2011) 2264–2269. P. Wehner, I. Shnitsar, H. Urlaub, A. Borchers, RACK1 is a novel interaction partner of PTK7 that is required for neural tube closure, Development 138 (2011) 1321–1327. F. Steinberg, M. Gallon, M. Winfield, E.C. Thomas, A.J. Bell, K.J. Heesom, J.M. Tavare, P.J. Cullen, A global analysis of SNX27retromer assembly and cargo specificity reveals a function in glucose and metal ion transport, Nat. Cell Biol. 15 (2013) 461–471. J.T. Eggenschwiler, K.V. Anderson, Cilia and developmental signaling, Annu. Rev. Cell Dev. Biol. 23 (2007) 345–373. S. Yuan, Z. Sun, Expanding horizons: ciliary proteins reach beyond cilia, Annu. Rev. Genet. 47 (2013) 353–376. I.R. Veland, R. Montjean, L. Eley, L.B. Pedersen, A. Schwab, J. Goodship, K. Kristiansen, S.F. Pedersen, S. Saunier, S.T. Christensen, Inversin/Nephrocystin-2 is required for fibroblast polarity and directional cell migration, PLoS One 8 (2013) e60193. M. Almuedo-Castillo, E. Salo, T. Adell, Disheveled is essential for neural connectivity and planar cell polarity in planarians, Proc. Natl. Acad. Sci. USA 108 (2011) 2813–2818. T. Yasunaga, K. Itoh, S.Y. Sokol, Regulation of basal body and ciliary functions by Diversin, Mech. Dev. 128 (2011) 376–386. E.K. Vladar, J.D. Axelrod, Disheveled links basal body docking and orientation in ciliated epithelial cells, Trends Cell Biol. 18 (2008) 517–520. L. Jakobsen, K. Vanselow, M. Skogs, Y. Toyoda, E. Lundberg, I. Poser, L.G. Falkenby, M. Bennetzen, J. Westendorf, E.A. Nigg, M. Uhlen, A.A. Hyman, J.S. Andersen, Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods, EMBO J. 30 (2011) 1520–1535. A.J. Ross, H. May-Simera, E.R. Eichers, M. Kai, J. Hill, D.J. Jagger, C. C. Leitch, J.P. Chapple, P.M. Munro, S. Fisher, P.L. Tan, H.M. Phillips, M.R. Leroux, D.J. Henderson, J.N. Murdoch, A.J. Copp, M. M. Eliot, J.R. Lupski, D.T. Kemp, H. Dollfus, M. Tada, N. Katsanis, A. Forge, P.L. Beales, Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates, Nat. Genet. 37 (2005) 1135–1140. F. Tissir, Y. Qu, M. Montcouquiol, L. Zhou, K. Komatsu, D. Shi, T. Fujimori, J. Labeau, D. Tyteca, P. Courtoy, Y. Poumay, T. Uemura, A.M. Goffinet, Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus, Nat. Neurosci. 13 (2010) 700–707. B. Guirao, A. Meunier, S. Mortaud, A. Aguilar, J.M. Corsi, L. Strehl, Y. Hirota, A. Desoeuvre, C. Boutin, Y.G. Han, Z. Mirzadeh, H. Cremer, M. Montcouquiol, K. Sawamoto, N. Spassky, Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia, Nat. Cell Biol. 12 (2010) 341–350.

] (]]]]) ]]]–]]]

11

[85] S. Nonaka, H. Shiratori, Y. Saijoh, H. Hamada, Determination of left-right patterning of the mouse embryo by artificial nodal flow, Nature 418 (2002) 96–99. [86] S. Nonaka, Y. Tanaka, Y. Okada, S. Takeda, A. Harada, Y. Kanai, M. Kido, N. Hirokawa, Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein, Cell 95 (1998) 829–837. [87] M.T. Boskovski, S. Yuan, N.B. Pedersen, C.K. Goth, S. Makova, H. Clausen, M. Brueckner, M.K. Khokha, The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality, Nature 504 (2013) 456–459. [88] E. Belotti, T.M. Puvirajesinghe, S. Audebert, E. Baudelet, L. Camoin, M. Pierres, L. Lasvaux, G. Ferracci, M. Montcouquiol, J.P. Borg, Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes, PLoS One 7 (2012) e46213. [89] J.P. Mahaffey, J. Grego-Bessa, K.F. Liem Jr., K.V. Anderson, Cofilin and Vangl2 cooperate in the initiation of planar cell polarity in the mouse embryo, Development 140 (2013) 1262–1271. [90] H.L. May-Simera, M. Kai, V. Hernandez, D.P. Osborn, M. Tada, P.L. Beales, Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish, Dev. Biol. 345 (2010) 215–225. [91] Y.H. Chien, M.E. Werner, J. Stubbs, M.S. Joens, J. Li, S. Chien, J.A. Fitzpatrick, B.J. Mitchell, C. Kintner, Bbof1 is required to maintain cilia orientation, Development 140 (2013) 3468–3477. [92] J. Ezan, L. Lasvaux, A. Gezer, A. Novakovic, H. May-Simera, E. Belotti, A.C. Lhoumeau, L. Birnbaumer, S. Beer-Hammer, J.P. Borg, A. Le Bivic, B. Nurnberg, N. Sans, M. Montcouquiol, Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton, Nat. Cell Biol. 15 (2013) 1107–1115. [93] B. Tarchini, C. Jolicoeur, M. Cayouette, A molecular blueprint at the apical surface establishes planar asymmetry in cochlear hair cells, Dev. Cell 27 (2013) 88–102. [94] M. Castelli, M. Boca, M. Chiaravalli, H. Ramalingam, I. Rowe, G. Distefano, T. Carroll, A. Boletta, Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis, Nat. Commun. 4 (2013) 2658. [95] M. Simons, M. Mlodzik, Planar cell polarity signaling: from fly development to human disease, Annu. Rev. Genet. 42 (2008) 517–540. [96] C. Jones, V.C. Roper, I. Foucher, D. Qian, B. Banizs, C. Petit, B.K. Yoder, P. Chen, Ciliary proteins link basal body polarization to planar cell polarity regulation, Nat. Genet. 40 (2008) 69–77. [97] D. Qian, C. Jones, A. Rzadzinska, S. Mark, X. Zhang, K.P. Steel, X. Dai, P. Chen, Wnt5a functions in planar cell polarity regulation in mice, Dev. Biol. 306 (2007) 121–133. [98] Y. Wang, N. Guo, J. Nathans, The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells, J. Neurosci. 26 (2006) 2147–2156. [99] B. Gao, Wnt regulation of planar cell polarity (PCP), Curr. Top. Dev. Biol. 101 (2012) 263–295. [100] N. Bin-Nun, H. Lichtig, A. Malyarova, M. Levy, S. Elias, D. Frank, PTK7 modulates Wnt signaling activity via LRP6, Development 141 (2014) 410–421. [101] A.C. Lhoumeau, F. Puppo, T. Prebet, L. Kodjabachian, J.P. Borg, PTK7: a cell polarity receptor with multiple facets, Cell Cycle 10 (2011) 1233–1236. [102] F. Puppo, V. Thome, A.C. Lhoumeau, M. Cibois, A. Gangar, F. Lembo, E. Belotti, S. Marchetto, P. Lecine, T. Prebet, M. Sebbagh, W.S. Shin, S.T. Lee, L. Kodjabachian, J.P. Borg, Protein tyrosine kinase 7 has a conserved role in Wnt/beta-catenin canonical signalling, EMBO Rep. 12 (2011) 43–49. [103] H. Peradziryi, N.A. Kaplan, M. Podleschny, X. Liu, P. Wehner, A. Borchers, N.S. Tolwinski, PTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling, EMBO J. 30 (2011) 3729–3740. [104] W. Lu, V. Yamamoto, B. Ortega, D. Baltimore, Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth, Cell 119 (2004) 97–108.

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005

12

E XP E RI ME N TAL CE L L R ES E ARC H

[105] L. Li, B.I. Hutchins, K. Kalil, Wnt5a induces simultaneous cortical axon outgrowth and repulsive axon guidance through distinct signaling mechanisms, J. Neurosci. 29 (2009) 5873–5883. [106] K.C. Corbit, A.E. Shyer, W.E. Dowdle, J. Gaulden, V. Singla, M.H. Chen, P.T. Chuang, J.F. Reiter, Kif3a constrains beta-catenindependent Wnt signalling through dual ciliary and non-ciliary mechanisms, Nat. Cell Biol. 10 (2008) 70–76. [107] T. Schwarz-Romond, C. Asbrand, J. Bakkers, M. Kuhl, H.J. Schaeffer, J. Huelsken, J. Behrens, M. Hammerschmidt, W. Birchmeier, The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling, Genes. Dev. 16 (2002) 2073–2084. [108] L. Azzolin, F. Zanconato, S. Bresolin, M. Forcato, G. Basso, S. Bicciato, M. Cordenonsi, S. Piccolo, Role of TAZ as mediator of Wnt signaling, Cell 151 (2012) 1443–1456. [109] X. Varelas, B.W. Miller, R. Sopko, S. Song, A. Gregorieff, F.A. Fellouse, R. Sakuma, T. Pawson, W. Hunziker, H. McNeill, J.L. Wrana, L. Attisano, The Hippo pathway regulates Wnt/betacatenin signaling, Dev. Cell 18 (2010) 579–591. [110] M. Imajo, K. Miyatake, A. Iimura, A. Miyamoto, E. Nishida, A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling, EMBO J. 31 (2012) 1109– 1122. [111] H. Yamanaka, T. Moriguchi, N. Masuyama, M. Kusakabe, H. Hanafusa, R. Takada, S. Takada, E. Nishida, JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates, EMBO Rep. 3 (2002) 69–75. [112] B. Ohkawara, C. Niehrs, An ATF2-based luciferase reporter to monitor non-canonical Wnt signaling in Xenopus embryos, Dev. Dyn. 240 (2011) 188–194. [113] B. Jung, A. Kohler, A. Schambony, D. Wedlich, PAPC and the Wnt5a/Ror2 pathway control the invagination of the otic placode in Xenopus, BMC Dev. Biol. 11 (2011) 36. [114] S. Narumiya, M. Tanji, T. Ishizaki, Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion, Cancer Metastasis Rev. 28 (2009) 65–76. [115] R. Levayer, T. Lecuit, Biomechanical regulation of contractility: spatial control and dynamics, Trends Cell Biol. 22 (2012) 61–81. [116] M. Williams, W. Yen, X. Lu, A. Sutherland, Distinct apical and basolateral mechanisms drive planar cell polarity-dependent convergent extension of the mouse neural plate, Dev. Cell (2014). [117] C.P. Heisenberg, Y. Bellaiche, Forces in tissue morphogenesis and patterning, Cell 153 (2013) 948–962. [118] X. Morin, Y. Bellaiche, Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development, Dev. Cell 21 (2011) 102–119. [119] M. Thery, A. Jimenez-Dalmaroni, V. Racine, M. Bornens, F. Julicher, Experimental and theoretical study of mitotic spindle orientation, Nature 447 (2007) 493–496. [120] A. Pitaval, Q. Tseng, M. Bornens, M. Thery, Cell shape and contractility regulate ciliogenesis in cell cycle-arrested cells, J. Cell Biol. 191 (2010) 303–312. [121] J. Lee, A. Andreeva, C.W. Sipe, L. Liu, A. Cheng, X. Lu, PTK7 regulates myosin II activity to orient planar polarity in the mammalian auditory epithelium, Curr. Biol. 22 (2012) 956–966. [122] A. Andreeva, J. Lee, M. Lohia, X. Wu, I.G. Macara, X. Lu, PTK7-Src signaling at epithelial cell contacts mediates spatial organization of actomyosin and planar cell polarity, Dev. Cell (2014).

] (]]]]) ]]]–]]]

[123] T. Nishimura, H. Honda, M. Takeichi, Planar cell polarity links axes of spatial dynamics in neural-tube closure, Cell 149 (2012) 1084–1097. [124] A. Robinson, S. Escuin, K. Doudney, M. Vekemans, R.E. Stevenson, N.D. Greene, A.J. Copp, P. Stanier, Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis, Hum. Mutat. 33 (2012) 440–447. [125] C.W. Chu, E. Gerstenzang, O. Ossipova, S.Y. Sokol, Lulu regulates Shroom-induced apical constriction during neural tube closure, PLoS One 8 (2013) e81854. [126] M. Simoes Sde, A. Mainieri, J.A. Zallen, Rho GTPase, and Shroom direct planar polarized actomyosin contractility during convergent extension, J. Cell Biol. 204 (2014) 575–589. [127] A. Shindo, J.B. Wallingford, PCP and septins compartmentalize cortical actomyosin to direct collective cell movement, Science 343 (2014) 649–652. [128] Z. Kibar, E. Torban, J.R. McDearmid, A. Reynolds, J. Berghout, M. Mathieu, I. Kirillova, P. De Marco, E. Merello, J.M. Hayes, J.B. Wallingford, P. Drapeau, V. Capra, P. Gros, Mutations in VANGL1 associated with neural-tube defects, N. Engl. J. Med. 356 (2007) 1432–1437. [129] A.R. Barker, R. Thomas, H.R. Dawe, Meckel-Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development, Organogenesis 10 (2014) 96–107. [130] A.C. Leightner, C.J. Hommerding, Y. Peng, J.L. Salisbury, V.G. Gainullin, P.G. Czarnecki, C.R. Sussman, P.C. Harris, The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity, Hum. Mol. Genet. 22 (2013) 2024–2040. [131] M. Cordenonsi, F. Zanconato, L. Azzolin, M. Forcato, A. Rosato, C. Frasson, M. Inui, M. Montagner, A.R. Parenti, A. Poletti, M.G. Daidone, S. Dupont, G. Basso, S. Bicciato, S. Piccolo, The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells, Cell 147 (2011) 759–772. [132] M.E. Feigin, S.D. Akshinthala, K. Araki, A.Z. Rosenberg, L.B. Muthuswamy, B. Martin, B.D. Lehmann, H.K. Berman, J.A. Pietenpol, R.D. Cardiff, S.K. Muthuswamy, Mislocalization of the cell polarity protein Scribble promotes mammary tumorigenesis and is associated with basal breast cancer, Cancer Res. (2014). [133] B.B. Williams, V.A. Cantrell, N.A. Mundell, A.C. Bennett, R.E. Quick, J.R. Jessen, VANGL2 regulates membrane trafficking of MMP14 to control cell polarity and migration, J. Cell Sci. 125 (2012) 2141–2147. [134] M. Kaucka, K. Plevova, S. Pavlova, P. Janovska, A. Mishra, J. Verner, J. Prochazkova, P. Krejci, J. Kotaskova, P. Ovesna, B. Tichy, Y. Brychtova, M. Doubek, A. Kozubik, J. Mayer, S. Pospisilova, V. Bryja, The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration, Cancer Res. 73 (2013) 1491–1501. [135] V. Luga, L. Zhang, A.M. Viloria-Petit, A.A. Ogunjimi, M.R. Inanlou, E. Chiu, M. Buchanan, A.N. Hosein, M. Basik, J.L. Wrana, Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration, Cell 151 (2012) 1542–1556. [136] E.S. Witze, E.S. Litman, G.M. Argast, R.T. Moon, N.G. Ahn, Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors, Science 320 (2008) 365–369.

Please cite this article as: M. Sebbagh, J.-P. Borg, Insight into planar cell polarity, Exp Cell Res (2014), http://dx.doi.org/10.1016/j. yexcr.2014.09.005