Retracing the path of planar cell polarity
© Schenkelaars et al. 2016
Received: 25 November 2015
Accepted: 22 March 2016
Published: 2 April 2016
The Planar Cell Polarity pathway (PCP) has been described as the main feature involved in patterning cell orientation in bilaterian tissues. Recently, a similar phenomenon was revealed in cnidarians, in which the inhibition of this pathway results in the absence of cilia orientation in larvae, consequently proving the functional conservation of PCP signaling between Cnidaria and Bilateria. Nevertheless, despite the growing accumulation of databases concerning basal lineages of metazoans, very few information concerning the existence of PCP components have been gathered outside of Bilateria and Cnidaria. Thus, the origin of this module or its prevalence in early emerging metazoans has yet to be elucidated.
The present study addresses this question by investigating the genomes and transcriptomes from all poriferan lineages in addition to Trichoplax (Placozoa) and Mnemiopsis (Ctenophora) genomes for the presence of the core components of this pathway. Our results confirm that several PCP components are metazoan innovations. In addition, we show that all members of the PCP pathway, including a bona fide Strabismus ortholog (Van gogh), are retrieved only in one sponge lineage (Homoscleromorpha) out of four. This highly suggests that the full PCP pathway dates back at least to the emergence of homoscleromorph sponges. Consequently, several secondary gene losses would have occurred in the three other poriferan lineages including Amphimedon queenslandica (Demospongiae). Several proteins were not retrieved either in placozoans or ctenophores leading us to discuss the difficulties to predict orthologous proteins in basally branching animals. Finally, we reveal how the study of multigene families may be helpful to unravel the relationships at the base of the metazoan tree.
The PCP pathway antedates the radiation of Porifera and may have arisen in the last common ancestor of animals. Oscarella species now appear as key organisms to understand the ancestral function of PCP signaling and its potential links with Wnt pathways.
KeywordsPlanar cell polarity Van Gogh Multigene families Porifera Placozoa Ctenophora Wnt signaling Metazoan phylogeny
Alternative names of PCP core components retrieved in metazoans and choanoflagellates. “No” means that the protein was not found. The asterisk indicates that even if no Fz was retrieved in Salpingoeca rosetta, the Fz family has been described in Fungi and Amoebozoa
Van Gogh (Vang) or Strabismus (Stbm)
Prickle (Pk) & Espinas (Esn)
Pkl1, 2, 3
Fzd3, 6, 7
Dvl or DvlA, B
Flamingo (Fmi) or Starry night (Stan)
Fmi or Celsr3L
Several evidences support that Wnt signaling regulates PCP in vertebrates  and Drosophila  even if precise mechanisms involved are so far misunderstood. In addition, various proteins have been identified as downstream effectors of the core pathway. For instance, Fuzzy (Fy) and Inturned (In) (Table 1) are potential additional effectors for the regulation of actin assembly at the basal body of cilia and are thus responsible for flagellum orientation (Fig. 1b) [5–8]. Various modules involving Rho GTPases, such as the Rho/Rock pathway, have been also described downstream of the core pathway [9, 10]. The Rho associated kinase (Rock) regulates acto-myosin dynamics (thought Myosin II phosphorylation) in order to induce changes in cell behavior (i.e. cell shape and cell adhesion). This explains why the down-regulation of the PCP core is often associated with defects in morphogenesis processes such as gastrulation or invagination (reviewed in ). Whereas they undoubtedly act in an intermingled way during animal development, the PCP core and the Rho/Rock modules now tends to be considered as two distinct modules [3, 11, 12]. For this reason, and because the presence and function of the Rho/Rock pathway has been recently investigated in sponges , the present study focuses on the origin of main PCP components (in addition to Fy and In) and only discusses the data in the light of what is known concerning the coordination of cell orientation in concerned organisms.
As recently reviewed by Hale and Strutt (2015) , the function of the PCP core proteins in epithelial cell orientation is well documented in various developmental processes across planulozoans (bilaterians + cnidarians) [14, 15]. Among those commonly used to study the planar polarized tissues in Drosophila are the alignment of actin hairs on the abdomen, the alignment of wing sensory bristles, and the arrangement of eye facet systems [16–18]. A further example of reliance on the PCP pathway can be found in the orientation of inner ear sensory hair cells and of hair follicles of vertebrate skin (Fig. 1c) [18–21]. Although the study of the planar polarity genes have been mainly focused on Drosophila and mammalians, some lines of evidence strongly support as well the involvement of the core PCP in cilia orientation in less conventional models. For instance, stbm knockdown experiments led to the dramatic disorganization of cilia in Planaria  and in the planula larva of the cnidarian Clytia hemisphaerica . Interestingly, these results imply that the PCP pathway was certainly already present in the last common ancestor of Bilateria and Cnidaria for patterning cell polarity processes.
Results and Discussion
Fz, Fy, Dgo and the PET family arose in the last common ancestor of Metazoa and Choanoflagellata
As previously reported , few members of the core PCP pathway were identified in the genome of the choanoflagellate Salpingoeca rosetta (Table 1 and Additional file 1). Indeed, our researches by TBLASN and domain analyses confirm that Dgo (Ankrd6 or Invs) and Fy proteins and the PET (Prickle/Espinas/Testin) family antedate the emergence of metazoans (Table 1). In contrast, these genes have not been retrieved so far in other unikonts such as Capsaspora owczarzaki (Filasterea), Spizellomyces punctatus, Allomyces macrogynus (Fungi) and Dictyostelium discoïdeum (Amoebozoa) [11, 31]. This strongly suggests that fy, dgo and the PET families were inherited from the last common ancestor of choanoflagellates and metazoans. We show here that several of these ancient genes may have been secondarily lost during animal evolution: no dgo orthologous gene was found in the genomes of Mnemiopsis leidyi and Trichoplax adhaerens, and no fy was identified in either of the glass sponge transcriptomes (Oopsacas minuta and Aphrocalistes vastus), whereas it is present in all other sponges studied here, including the Amphimedon queenslandica genome in which it had previously been considered as missing (Table 1 and Additional file 1) . Concerning the Fz family, even if no orthologous protein was retrieved in S. rosetta, some authors have recently reported sequences that may belong to the Fz family in Fungi and Amoebozoa [29, 30], suggesting that this protein family was already present in the last common ancestor of unikonts. Furthermore our recent study supports that the last common ancestor of metazoans certainly already possessed two ancestral paralogs (FzdA and FzdB) while two duplication events would have occurred just before the radiation of Cnidarians .
Evolution of the Prickle/Espinas/Testin (PET) family
Interestingly, only one sequence belonging to the PET family was retrieved in Porifera, Ctenophora and Choanoflagellata (Fig. 3a). We named this single protein PkTesL and it is devoid of the long C-term tail. This strongly suggests that a unique ancestral prickle/testin-like copy was already present in the last common ancestor of metazoans and choanoflagellates. A duplication event and the addition of the tail may then have occurred in the last common ancestor of cnidarians, bilaterians and placozoans, resulting in the coexistence of the two paralogous genes, pk and tes (Fig. 3b). Nevertheless, only pk paralog has been retrieved in Placozoa, which implies that tes may subsequently have been lost in this lineage.
As mentioned above, it has been suggested that Tes interacts with VangL2 to regulate inner ear sensory cell orientation in mice , which suggests that Pk and Tes may have retained partial functional redundancy, both being involved in planar cell polarity mechanism. Thus, even if the functional role of PkTesL proteins remains to be tested in Porifera and Ctenophora through functional studies, the involvement of both Pk and Tes in cell orientation allows us to propose that it is an ancestral role of the PET family.
Evolution of the inversin family
Potential convergence of In-like protein with metazoan Inturned
We retrieved the In protein in almost all metazoan databases explored here (Table 1 and Additional file 1). Nevertheless, no In was detected in M. leidyi genome, suggesting that it is absent from Ctenophores and implying that it may have been secondarily lost by this lineage (depending on the phylogenetic scenario considered).
Although in has been considered as a metazoan innovation , we obtained conflicting results which made the data difficult to interpret in the present study. Indeed, TBLASTN against the S. rosetta genome and reverse TBLASTN against the NCBI database weakly supports (e-value: 0.014) the assignation of PTSG_12265.1 to the In family (Additional file 1). This sequence, called here InL, contains residues which are quite similar (ELYVCF and EMAFKLFS) to those of the two final motifs of In proteins (Additional file 2), suggesting that metazoan In and InL of choanoflagellates may have arisen from an ancestral protein. This suggests that the emergence of in dates back to the last common ancestor of choanoflagellates and metazoans. Nevertheless, no PDZ domain was predicted for this sequence and no similarity to the In family was found among the 566 remaining residues of the protein (7.02 % sequence identity) (Additional file 2). In addition, no match for the choanoflagellate InL (cutoff 1.0) was found in the genome of M. brevicollis, suggesting that the protein found in S. rosetta may represent a convergent feature or that it was lost in M. brevicollis.
Dsh, Fmi and Stbm emerged during metazoan evolution
In contrast to other genes, no obvious evidence of dsh, fmi or stbm has thus far been provided outside metazoans . These genes appear, therefore, to be innovations of the metazoan lineage. The question remains as to when they actually appeared during metazoan evolution. Previous studies have shown that dsh belongs to the metazoan ancestral molecular toolkit, being present in all metazoan lineages studied so far (Bilateria, Cnidaria, Placozoa, Porifera and Ctenophora) [26–28, 31]. Nevertheless, no dsh ortholog was found in the transcriptomic data of the glass sponge O. minuta. Interestingly, a previous study on Aphrocalistes vastus (belonging to the same sponge lineage, Hexactinellida) led to the same observation , suggesting loss in this lineage.
In summary, the present study shows that fmi and stbm appear to be absent in ctenophores  and hexactinellids whereas sponges belonging to Calcarea and Demospongiae possess only fmi. Thus, the homoscleromorph is the only poriferan class that possesses all the genes previously described as the PCP core. This means that both fmi and stbm were already present in the last common ancestor of Bilateria, Cnidaria, Placozoa and Homoscleromorpha. According to the most recent phylogenetic relationships, showing the monophyly of Porifera and Homoscleromorpha as the sister group of calcareous sponges [25, 36, 37], our findings suggest that the whole set of PCP components was present in the poriferan ancestor and were subsequently lost. The interpretation of the absence of both genes in ctenophores (ancestral absence or losses) depends on the position of this lineage (sister group of all other animals or not).
The search of the ancestral function of the PCP core
The concept of core PCP module describes a group of Drosophila genes that when mutated yield polarity defects. However, it appears that all these genes do not behave in the same way. In fact, one may choose to split them into three or four groups or maybe as many as components of the core. Briefly, the 1) Fmi protein, is totally indispensable, its absence stops any planar signaling (and consequently no polarity can be propagated); 2) Fzd is not indispensable for PCP signaling between two adjacent cells but it is needed for propagation of PCP signaling through several cells; 3) Stbm is necessary for strong intercellular signaling as well as for strong propagation of polarity, and finally 4) a fourth group could correspond to genes which are perfectly dispensable for both signaling and propagation [38, 39]. According to this possible functional interpretation, the keeping of a quintessential core composed of Fzd and Fmi in all poriferan lineages (except in Hexactinellida devoid of Fmi) may reflect a functional constraint. This observation calls for functional experiments on the coordinated beating of oriented cilia in the larva of sponges in order to highlight if whether or not Fzd and Fmi are sufficient to induce planar cell orientation. Nevertheless, the differences of gene content (whole set of genes in Homoscleromorpha, no Vang but the Fzd/Fmi couple in Calcarea and Demospongiae and no Fmi and no Vang in glass sponges) is hardly explained by the presence of oriented cilia in all sponge larvae. Furthermore, observing a coordinated beating of ciliated comb rows in ctenophores while no PCP pathway was identified (no Stbm and no Fmi), also supports that other mechanisms are certainly responsible for the planar orientation of tissues in basally branching animals (e.g. water flow or the Ft-Ds-Fj pathway).
Limits in gene prediction
Several proteins of the PCP pathway, especially Fmi and Inv, were not retrieved in some databases studied here, implying that they may have been subsequently lost in various lineages. However, it is possible that we were simply not able to identify them due to i) sequence divergence, ii) incomplete databases or iii) because of their composition in highly recurrent domains. For instance, Ankyrin repeats are one of the most common protein-protein interaction motifs in eukaryotes [40–42], resulting in bias in TBLASTN analyses to detect Invs. In addition, if we admit that diego is the Drosophila functional equivalent of ankrd6 or invs (as proposed in Clytia) , this means that the encoded protein would have a highly divergent domain composition (only 6 ANK repeats and no IQ domain in Dgo) in addition to a low amino acid conservation, without affecting its function .
In addition, the absence of fmi in various species will have to be verified against additional databases. fmi are long genes split by numerous introns, making more difficult their genomic assembling and identification. For instance, Scfmi is a 20 kb genomic sequence consisting of 22 exons for more than 8 kb of coding sequences (Additional file 2). In addition, the numerous Cadherin domains and the high level of divergence of corresponding sequences may still prevent their detection, even when transcriptomic libraries are used.
In contrast, Stbm/Vang is a well-conserved protein that does not contain highly recurrent domains. Furthermore, they are encoded by genes without introns (e.g. O. carmela and T. adharens). It thus seems very unlikely that the non-prediction of this gene is due to software and algorithmic limitations. In addition, retrieving vang in all Oscarella databases (including transcriptomes obtained independently by different teams) but not in other sponges (including the genomes of A. queenslandica and S. ciliatum) or in the M. leidyi genome suggests that our results, like previous findings concerning this gene, [24, 25], are not due to the low coverage of databases, and are thus reliable.
Multigene families as possible characters to support phylogenetic scenarios
By examining a large dataset of non bilaterian metazoans, the present study challenges previous statements concerning the origin of the Planar Cell Polarity pathway. Although previous studies of the genomes of M. leidyi and A. queenslandica suggested that the PCP pathway arose in the last common ancestor of Bilateria, Cnidaria and Placozoa, our results allow us to state that this pathway dates back at least to the emergence of Porifera. More specifically, we describe here bona fide Stbm/Vang and Fmi proteins in sponges from the Oscarella genus (Homoscleromorpha class), whereas other lineages lack few players of the PCP pathway. This discovery spotlights the retrieval of a unique, complete PCP pathway - in Homoscleromorph sponges - and thus calls for functional studies in this particular sponge lineage to investigate the mechanisms involved in the coordination of cell orientation in a non planulozoan lineage (Bilateria + Cnidaria). Nevertheless, whether or not the absence of key proteins means that no PCP mechanisms occurs in other sponge lineages also requires investigation. The present study provides yet another strong affirmation that each sponge lineage is of high interest to gain a better understanding of the evolution of key molecular toolkits in metazoans. Finally, this study highlights how the accumulation of data concerning the evolution of multigene families may help us to trace early metazoan evolution when no phylogenetic consensus is currently accepted.
The main components of the Planar Cell Polarity pathway were researched in different transcriptomic or genomic databases: Demospongiae (Amphimedon queenslandica and Ephydatia muelleri), Hexactinellida (Aphrocalistes vastus and Oopsacas minuta), Calcarea (Sycon ciliatum), Homoscleromorpha (Oscarella lobularis, Oscarella carmela and Oscarella sp.), Mnemiopsis leidyi (Ctenophora), Trichoplax adhaerens (Placozoa) and Salpingoeca rosetta (Choanoflagellata). Most of these databases are available online (Additional file 1). When genes were absent from Mnemiopsis leidyi or Salpingoeca rosetta, we investigated the closely related species Pleurobrachia pileus and Monosiga brevicollis, respectively.
We searched proteins of interest by local TBALSTN analyses using BioEdit software and Mus musculus sequences . In order to retrieve highly divergent sequences, a 1.0 threshold e-value was fixed. The relevance of our results was then tested using a reciprocal best hit approach  against the NCBI database (nr/nt) (with no restriction to a specific taxa) and via protein domain analyses using InterProScan5 (http://www.ebi.ac.uk/Tools/pfa/iprscan5/). When no orthologous sequences were obtained using Mus musculus sequences, similar methodology was applied using Clytia hemisphaerica (Cnidarian) or Amphimedon queenslandica (Porifera) sequences [23, 24].
Since the Prickle/Testin and Inversin/Diego families are multigene families, phylogenetic analyses were performed for sequence assignation to each orthologous group. Protein alignments were carried out using the ClustalW function of BioEdit . Alignments were then controlled visually and slightly improved before being cut to conserve only functional domains (i.e. LIM domains for the Prickle/Testin family and ANK domains for Invs proteins) (full alignments are available in Additional file 1). Maximum likelihood (ML) analyses were performed using the online PhyML software (www.atgc-montpellier.fr)  and branch supports were estimated using 1000 bootstrap re-sampling (all other default parameters were conserved). Bayesian analyses were performed using MrBayes v3.2.2  with one cold chain and three heated chains until the average deviation of split frequencies was below 0.01 (100 000 generations). As recommended by ProtTest 3.2 , both ML and Bayesian analyses were performed using the WAG substitution model.
This work has been carried out thanks to the support of the A*MIDEX project (n°ANR-11-IDEX-0001-02) funded by the ‘Investissements d’Avenir’ French Government program, managed by the French National Research Agency (ANT). This university foundation A*MIDEX supports the ‘Spongex’ project in order to develop the poriferan models Oscarella lobularis and Oopsacas minuta. The authors thank Dr. G. Woerheide for the transcriptome assembly of O. minuta and Dr. E. Gazave and R. Mackie for reading and improving this manuscript.
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