FGFRL1 is a neglected putative actor of the FGF signalling pathway present in all major metazoan phyla
© Bertrand et al; licensee BioMed Central Ltd. 2009
Received: 2 March 2009
Accepted: 9 September 2009
Published: 9 September 2009
Fibroblast Growth Factors (FGF) and their receptors are well known for having major implications in cell signalling controlling embryonic development. Recently, a gene coding for a protein closely related to FGFRs (Fibroblast Growth Factor Receptors) called FGFR5 or FGFR-like 1 (FGFRL1), has been described in vertebrates. An orthologous gene was also found in the cephalochordate amphioxus, but no orthologous genes were found by the authors in other non-vertebrate species, even if a FGFRL1 gene was identified in the sea urchin genome, as well as a closely related gene, named nou-darake, in the planarian Dugesia japonica. These intriguing data of a deuterostome-specific gene that might be implicated in FGF signalling prompted us to search for putative FGFRL1 orthologues in the completely sequenced genomes of metazoans.
We found FGFRL1 genes in the cnidarian Nematostella vectensis as well as in many bilaterian species. Our analysis also shows that FGFRL1 orthologous genes are linked in the genome with other members of the FGF signalling pathway from cnidarians to bilaterians (distance < 10 Mb). To better understand the implication of FGFRL1 genes in chordate embryonic development, we have analyzed expression patterns of the amphioxus and the mouse genes by whole mount in situ hybridization. We show that some homologous expression territories can be defined, and we propose that FGFRL1 and FGF8/17/18 were already co-expressed in the pharyngeal endoderm in the ancestor of chordates.
Our work sheds light on the existence of a putative FGF signalling pathway actor present in the ancestor of probably all metazoans, the function of which has received little attention until now.
Interaction between many different signalling pathways is necessary to form a metazoan starting from a single egg cell. Fibroblast Growth Factor (FGF) signalling represents one such developmental pathway. FGFs are small proteins that act by binding to their transmembrane receptors, FGFRs. The latter are characterised by three Immunoglobulin-like (Ig-like) extracellular domains, which are implicated in ligand and heparan sulphate binding, as well as an intracellular tyrosine kinase domain responsible for signal transduction. In mammals, the analysis of several completely sequenced genomes shows the presence of 22 FGF and 4 FGFR genes . Interestingly, FGFs and FGFRs arose early in metazoan evolution, since conserved genes for the two families are present in the genomes of diploblastic animals like the sea anemone Nematostella vectensis .
Besides the 4 classical FGFRs known in mammals, a fifth evolutionarily related protein, called FGFR5 or FGFR-like 1 (FGFRL1), has recently been described in vertebrates [3–8]. FGFRL1 displays the same structural organization as FGFRs, with the exception of the cytoplasmic tyrosine kinase domain. Indeed, this receptor has a signal peptide followed by three Ig-like loops and a transmembrane domain. The cytoplasmic part of the protein is not related to tyrosine kinases and does not show any known structural feature that could help to understand its function. Using GFP-fused receptors, it was shown that FGFRL1 is localised to the membrane, and FRET assays showed that FGFRL1 forms homodimers through interactions implicating both the extracellular and intracellular domains . However, using the same technique, no interaction between FGFRL1 and FGFRs could be detected . Moreover, a variety of assays show that FGFRL1 is able to bind at least FGF2, but with lower affinity than FGFRs, and that it also seems to interact with heparan sulphate [4, 6]. In light of all these data, it was proposed that FGFRL1 might act as a "decoy" receptor for FGFR by trapping FGFs.
Gene inactivation experiments performed in mouse and zebrafish have shed light on the possible in vivo function of FGFRL1 during development [5, 10–12]. In Danio rerio, two copies of FGFRL1 have been identified, fgfrl1a and fgfrl1b, which probably arose after the genome duplication that took place early in the evolution of actinopterygian fish lineage . Injection of morpholinos targeting one or both duplicates leads to defects in cartilage formation of the pharyngeal arches . No other defects were described, a surprising result given that fgfrl1a and fgfrl1b mRNAs are detected in other organs such as pectoral fin buds and lens, as well as in the midbrain-hindbrain boundary. However, fgfrl1a-morpholino injected embryos have a phenotype resembling that of FGF3 mutants that is not consistent with a putative dominant negative activity of FGFRL1 . On the other hand, the first knock-out mutant mice described for the FGFRL1 gene show a very mild phenotype in homozygous embryos . Indeed, newborns seem normal but die one hour after birth due to respiratory failure associated with an abnormally-formed diaphragm. However, a recent publication, describing the phenotype of other knock-out mutant mice for the FGFRL1 gene, shows that disrupting this gene also leads to craniofacial defects . This suggests that the implication of FGFRL1 in pharyngeal development may be conserved in vertebrates.
An orthologue of FGFRL1 was isolated in the cephalochordate amphioxus Branchiostoma floridae , but searches for orthologous genes in the completely sequenced genomes of other non vertebrates were unsuccessful. This was surprising given the description of the nou-darake gene in the planarian Dugesia japonica, which clearly shows a structure related to FGFRL1 . It was therefore proposed that FGFRL1 was specific to the chordate lineage. However, an FGFRL1 orthologue was later identified in the genome of the sea urchin . In order to gain insight into the origin and evolution of the FGFRL1 gene family, we performed an exhaustive Blast analysis. We found at least one FGFRL1 orthologue in many invertebrate species, including the nematode Caenorhabditis elegans, the sea squirt Ciona intestinalis, and the crustacean Daphnia pulex. We also identified a clear FGFRL1 orthologue in the genome of Nematostella vectensis. To further analyse the role of this gene, which has been conserved from diploblastic animals to mammals, and to better understand its ancestral function in chordates, we characterised mRNA expression during amphioxus embryonic development, as well as in early embryonic stages in mouse. Our data highlight two embryonic regions that might correspond to FGFRL1 expression territories in the ancestor of chordates, namely the pharyngeal endoderm and the anterior neural tissues. Finally, our work sheds light on a possible new actor of the FGF signalling pathway that has been poorly studied until now, particularly outside vertebrates.
Nou-darake from Dugesia japonica is a real FGFRL1 orthologue
These findings clearly establish that FGFRL1 is not only present in chordates and echinoderms, but also in lophotrochozoans. Although the possibility of a high rate of gene loss in many animals cannot be excluded, it was surprising that no orthologue was found in any completely sequenced genome except for those of vertebrates and of the sea urchin. We therefore undertook a more detailed analysis of the other available genomes.
FGFRL1 orthologues are present in many metazoans
Species for which we searched for FGFRL1 putative orthologues.
Number of orthologues
Capitella sp. I
Putative FGFRL1 orthologues.
Best reciprocal Blast with vertebrates
SP (1-23), Ig (62-174), Ig (192-301), TM (317-339)
T. rubripes FGFRL1a (CAH03726)
SP (1-30), Ig (42-154), Ig (178-267), TM (298-320)
T. rubripes FGFRL1a (CAH03726)
SP (1-17), Ig (35-99), Ig (145-211), Ig (236-340), TM (367-389)
X. laevis FGFRL1 (AAI69825)
Ig (2-50), Ig (103-166), Ig (210-301), TM (325-347)
D. rerio FGFRL1b (CAH03196)
SP (1-19), Ig (47-114), Ig (164-225), Ig (267-374), TM (388-410)
R. norevegicus FGFRL1 (NP_954545)
SP (1-18), Ig (47-115), Ig (165-226), Ig (268-375), TM (389-411)
R. norevegicus FGFRL1 (NP_954545)
Capitella sp. I
SP (1-21), Ig (39-103), Ig (166-234), Ig (265-352), TM (386-408)
D. rerio FGFRL1a (NP_956670)
Ig (12-77), Ig (138-202), Ig (227-336)
H. sapiens FGFRL1 (AAK26742)
Ig (15-80), Ig (137-201), Ig (226-335)
R. norevegicus FGFRL1 (NP_954545)
SP (1-19), Ig (37-101), Ig (157-222), Ig (253-339), TM (370-392)
SP (1-22), Ig (39-103), Ig (164-227), Ig (258-355), TM (375-397)
SP (1-23), Ig (40-106), Ig (153-239), Ig (272-379), TM (419-441)
G. gallus FGFRL1 (NP_989787)
SP (1-27), Ig (38-121), Ig (164-236), Ig (259-373), TM (386-408)
D. rerio FGFRL1b (AAI62498)
Ig (18-82), Ig (150-211), Ig (236-343)
X. laevis FGFRL1 (AAI69825)
SP (1-19), Ig (34-123), Ig (161-225), Ig (249-367), TM (380-402)
T. rubripes FGFRL1a (CAH03726)
SP (1-29), Ig (38-137), Ig (159-275), TM (306-328)
D. rerio FGFRL1b (CAM60089)
SP (1-17), Ig (26-125), Ig (147-263), TM (293-315)
H. sapiens FGFRL1 (AAK26742)
SP (1-18), Ig (36-100), Ig (157-222), Ig (253-339), TM (370-392)
SP (1-24), Ig (42-106), Ig (163-228), Ig (259-356), TM (377-399)
SP (1-31), Ig (48-113), Ig (167-231), Ig (262-349), TM (381-403)
X. tropicalis FGFRL1 (NP_001011189)
SP (1-20), Ig (38-102), Ig (159-224), Ig (255-341), TM (372-394)
SP (1-28), Ig (44-122), Ig (175-240), Ig (277-388), TM (417-439)
T. nigroviridis FGFRL1b (CAG10558)
Ig (69-133), Ig (192-255), Ig (280-382), TM (415-437)
H. sapiens FGFRL1 (AAK26742)
Ig (15-79), Ig (135-204), Ig (235-321), TM (352-374)
Ig (20-84), Ig (143-208), Ig (239-325), TM (356-378)
Ig (18-84), Ig (115-200), TM (231-253)
Ig (22-86), Ig (145-210), Ig (241-327), TM (358-380)
SP (1-17), Ig (37-125), Ig (142-241), TM (253-275)
T. rubripes FGFRL1a (CAH03726)
SP (1-21), Ig (36-100), Ig (157-222), Ig (253-391), TM (369-391)
The domain organization of the different putative orthologues is given in Table 2, according to the SMART online software [16, 17]. All the sequences that are full-length possess three Ig loops, except those found in insects. Indeed, for all insects that we analyzed, putative FGFRL1 orthologous proteins only have two Ig loops between their signal peptide and transmembrane domain.
FGFRL1 gene organization is conserved between cnidarians and vertebrates
In the deuterostome group, although not all gene predictions are complete, the exon/intron structure is also quite similar to that of vertebrates, except in the urochordates. Indeed, in the sea urchin the only obvious difference is that the box between IgI and IgII is coded by four exons instead of one. In amphioxus, it is the IgII domain that is cut into two exons compared to one in vertebrates and sea urchin . For the two Ciona species, the exon/intron data available are incomplete; however, we observed that the gene organization is clearly not conserved with that of the other deuterostomes. Indeed, the three Ig loop coding domains are separated into two exons.
In lophotrochozoans (a mollusc Lottia gigantea and an annelid Capitella species I), the gene structure is close to that observed for both vertebrates and the sea anemone. In effect, only what corresponds to the first exon is separated into two sections, as well as the IgIII domain coding part, which is split into two exons.
In contrast, the gene structure of all ecdysozoan FGFRL1 orthologues is very different. For C. elegans and C. briggsae, IgI and IgII domains are each encoded by two exons, whereas the end of IgII, IgIII, the transmembrane domain and part of the cytoplasmic domain are encoded by a unique exon. The last exon codes for the end of the cytoplasmic domain and for the 3'UTR. In Drosophila, the first Ig domain is encoded by two exons, while the IgII domain, the transmembrane and cytoplasmic domains as well as the 3'UTR are encoded by a unique exon. In the other insects, for which the gene organization data are incomplete, the exon/intron structure is similar to what is observed in Drosophila. Finally, in Daphnia pulex, all the Ig domains are encoded by several exons in the three genes found in its genome. The divergence of the genomic structure in several ecdysozoan lineages compared to vertebrates and diploblastic animals has previously been described, and it seems that the FGFRL1 orthologues are no exception .
Genomic linkage of FGFRL1 and genes involved in FGF signalling
FGFRL1 expression during amphioxus and mouse embryogenesis
To better understand the putative implication of FGFRL1 during embryonic development in chordates, we chose to analyze its expression pattern by whole mount in situ hybridization in two species: amphioxus, a cephalochordate placed at the base of the chordate clade; and mouse, a vertebrate for which only late embryonic expression has been described .
FGFRL1 appeared early during metazoan evolution and was linked to genes of the FGF signalling pathway
First, our analysis of the planarian nou-darake sequence supported its bona fide orthology to the chordate FGFRL1 genes. Our subsequent search for other orthologues in complete genomes led us to identify FGFRL1 genes in many metazoan species. Although the position in the phylogenetic reconstructions is not well supported for thediploblastic sequences, the conserved structure of the protein and of the gene in Nematostella vectensis, and of the genomic position in insects, together with the reciprocal blast results, highly support the fact that these genes are FGFRL1 orthologues in these species. As we were unable to find FGFRL1 genes outside metazoans, even in the choanoflagellate Monosiga brevicolis genome, we conclude that FGFRL1 appeared early during metazoan evolution, and was present at least in the common ancestor of bilaterian and diploblastic animals, as is also the case for the FGF and FGFR gene families .
In our analysis of the genomic environment of FGFRL1 genes, we found that they are in the vicinity of FGF8/17/18 or FGFR, or both, in many genomes. It has previously been suggested that FGFR8/17/18 and FGFR orthologous genes were probably linked in the ancestor of bilaterian animals [1, 21]. We propose that the FGFRL1 orthologue was also part of the same syntenic block in Urbilateria. In Nematostella vectensis, the NvSprouty gene is located between the FGFRL1 gene and the FGF8a gene (at position 1,09 Mb in the scaffold 51 represented in Figure 4) . Sprouty homologues in vertebrates and Drosophila are known to be negative regulators of FGF signalling , and in Nematostella, expression of NvSprouty overlaps with that of several FGF ligands. It has therefore been proposed that the FGF-Sprouty feedback loop is conserved between cnidarian and bilaterian animals . The fact that FGFRL1 is linked to FGF signalling genes in the genomes of cnidarians to bilaterians suggests that it may play a role in this pathway, although this still needs to be clearly demonstrated. Some functional data in the planarian Dugesia japonica indicates that this might be the case during regeneration in this species . Indeed, expression data and RNAi experiments show that the FGFRL1 orthologue nou-darake is implicated in brain tissue induction during regeneration and that this induction is suppressed by double-strand RNA injection for FGFR1 and FGFR2. Moreover, overexpression of nou-darake in Xenopus embryos leads to developmental phenotypes that are very similar to those obtained after overexpression of XFD, a dominant-negative FGF receptor. Although the biochemical function of nou-darake still needs to be elucidated, it was subsequently proposed that it might be a modulator of FGF signalling .
FGFRL1 embryonic expression sheds light on putative conserved and non-conserved functions in chordates
In vertebrates, the embryonic expression pattern of FGFRL1 has already been investigated in Xenopus  and in zebrafish, which possesses two genes, fgfrl1a and fgfrl1b [5, 10]. In Xenopus as in mouse, FGFRL1 expression starts at the gastrula stage, whereas neither of the zebrafish duplicates is expressed before somitogenesis. However, in Xenopus, expression is restricted to the anterior region of the gastrula whereas we have found anterior and posterior expression in mouse. This disparity may reflect a difference in the early function of the FGFRL1 orthologues in these species, or may reflect the fact that the gastrulation process is divergent in mouse, zebrafish and Xenopus. During later stages, expression in the telencephalon, branchial arches, otic vesicle, and somites is shared among mouse and Xenopus FGFRL1 and zebrafish fgfrl1a. However, in zebrafish, expression in somites is transient whereas in mouse and Xenopus, expression starts early and continues into late development. In Xenopus, although expression is detected in the mid-hindbrain boundary and in the lens, as for zebrafish fgfrl1a and fgfrl1b respectively, this is not the case in mouse. While some expression domains appear conserved among the three vertebrates, the presence of clear differences suggests the existence of conserved and non-conserved functions during vertebrate development.
Interestingly, amphioxus and vertebrate FGFRL1 expression patterns share some similarities. Indeed, in the gastrula stage embryos of amphioxus, we observed high expression in the anterior part, similarly to what has been described in Xenopus. At later stages, expression in the cerebral vesicle and in parts of the pharyngeal endoderm in amphioxus can be considered as homologous to the expression in the anterior brain and in the branchial arches anlagen in Xenopus, zebrafish and mouse. However, the somites do not express FGFRL1 in amphioxus, a surprising result given that it is clearly detected at least transitorily in all vertebrates studied. It has also been proposed that FGFRL1 might be implicated in cartilage formation in vertebrates, and morpholino injection in zebrafish shows that both duplicates fgfrl1a and fgfrl1b play a role during pharyngeal arch development . In vertebrates FGF3 and FGF8 are expressed in pharyngeal endoderm where they induce cartilage formation. Amphioxus does not have cartilage but, like FGFRL1, FGF8/17/18 is expressed in the pharyngeal endoderm , although overlap of their expression domains is not complete. On the other hand, as described recently in amphioxus, there is not a broad coexpression of cartilage marker genes in this region of the embryo . These data might suggest that FGF8/17/18 and FGFRL1 coexpression in the pharyngeal endoderm, the first sign of a possible interaction between the two, was already present in the chordate ancestor, and that the two genes were recruited in vertebrates for cartilage formation in this region of the embryo.
Conflicting functional data in vertebrates
Although the expression data we have obtained in mouse might indicate that FGFRL1 is implicated in cartilage formation, as is the case in zebrafish, the functional data that were available until very recently did not support this hypothesis. In zebrafish, morpholino injections for the two duplicates fgfrl1a and fgfrl1b show that they have a function in pharyngeal arch formation . In contrast, knock-out (KO) of FGFRL1 in mouse, as first described by Baertschi and collaborators, caused animals to die early after birth due to respiratory failure associated with diaphragm alteration . These animals do not show obvious skeletal abnormalities in spite of specific embryonic expression of FGFRL1 in cartilage anlagen. However, some data suggested that in human, as in zebrafish, FGFRL1 might be implicated in facial cartilage formation during embryogenesis. For example, two human patients having facial malformations caused by the deletion of the FGFRL1 gene, or by a frameshift mutation in its intracellular coding part, have been described [26, 27]. These data, together with the results obtained in zebrafish, made the absence of skeletal abnormalities after FGFRL1 gene inactivation in mouse really puzzling. Finally, knock-out mutant mice, using a different construct, show craniofacial defects in addition to diaphragm malformations . This strongly suggests that FGFRL1 implication in pharyngeal cartilages development is conserved in vertebrates, and that the first mutant described in mouse did not show a phenotype corresponding to full inactivation of this gene. Such a discrepancy could result from the inefficacy of the construct used to create the first FGFRL1 KO mutants, which only deletes exon 0 and exon 1, corresponding to the 5' UTR and to the signal peptide coding part of the mouse gene. Exons encoding the three Ig loops, as well as the transmembrane and cytoplasmic domains, are still present in mutant mice. One could imagine that an mRNA might be produced from an alternative 5' UTR, leading to partial protein production and function. This could explain the mild phenotype observed in these mutants compared to the more recently published ones.
Our work shows for the first time that FGFRL1 has clear orthologues in many metazoan species, which is in stark opposition to previously published data [13, 27]. Given the structural similarity of the FGFRL1 protein to FGFRs, and its genomic linkage with other members of the FGF signalling pathway from cnidarians to bilaterians, it is reasonable to propose that FGFRL1 is an actor of this pathway in metazoans, thus far neglected due to its supposed inexistence outside deuterostomes. The expression data in chordates support a conserved function in the pharyngeal endoderm, which has been shown in zebrafish by morpholino injections, and, more recently, by knock-out mutant constructs in mouse.
Data on the embryonic role of FGFRL1 orthologues outside the chordate group remain sparse. In the FlyBase database , we have found the expression pattern of the Drosophila FGFRL1 gene (named CG31431), but it is still unpublished. The expression pattern is very restricted throughout embryogenesis, which might indicate a specific function that still needs to be studied. With respect to Caenorhabditis elegans, we looked at the data available in WormBase  for the FGFRL1 orthologous gene (named Y102A11A.8). There is no embryonic expression description, and there is an absence of specific phenotype described for one RNAi experiment . In planarians, no embryonic expression has been described, but functional data in Dugesia japonica strongly suggest interaction between FGFRL1 and FGF signalling during regeneration. Our work reveals the existence of a widely conserved gene, FGFRL1, whose characteristics may shed light on the most ancestral FGF functions. Detailed developmental studies are needed to decipher its full evolutionary history and the diversification of FGF signalling pathways in metazoans.
Genomic and databases sequences survey
We searched for FGFRL1 orthologous sequences using Blast with the mouse FGFRL1 peptide sequence and the planarian nou-darake sequence . We first used BlastP on the predicted peptides and then TBlastN on the genomic sequences. We also used BlastP on Genbank sequences to look for more putative orthologues. The sequences obtained were then analyzed by BlastP to exclude false-positives. The genomic databases used are listed in Table 1.
Predicted amino acid sequences were aligned automatically using ClustalW  with manual correction in Seaview . Phylogenetic reconstruction was done using amino acid alignments of the longest sequences found for each gene. Only complete sites (no gap, no X) were used. Phylogenetic trees were built using RaxML, under the JTT+I+G model, with 100 bootstrap repetitions on the Cipres Portal v1.15 .
Isolation of FGFRL1 cDNA
Partial cDNAs from B. lanceolatum and mouse FGFRL1 were cloned by RT-PCR on adult RNA in pGEM-T Easy vector (Promega). An insert was then subcloned in pBluescript II SK (Stratagene) for subsequent RNA probe synthesis. Accession number for the B. lanceolatum sequence is FJ694966.
Whole mount in situ hybridization
Ripe animals of the Mediterranean amphioxus (B. lanceolatum) were collected in Argelès-sur-Mer (France), and gametes were obtained by heat stimulation [35, 36]. Fixation and whole-mount in situ hybridization were performed as described in , except the chromogenic reaction which was performed using BM Purple . Mouse embryos were dissected in PBS, fixed in 4% paraformaldehyde (PFA) and whole mount in situ hybridization was performed according to .
We thank Nicolas Fossat for his helpful comments. We are grateful to Association pour la Recherche contre le Cancer, Centre National de la Recherche Scientifique, the European Molecular Biology Organization, and the Cascade network of excellence in the 6th Framework Programme for financial support. The laboratory of HE is supported by the Cascade EU Network of Excellence and Agence Nationale de la Recherche. The laboratory of JGF is supported by BMC2008-03776 (Ministerio de Educación y Ciencia). IS' postdoctoral position was supported by a CNRS fellowship. SB's postdoctoral position was supported by an ARC fellowship.
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