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FGFRL1 is a neglected putative actor of the FGF signalling pathway present in all major metazoan phyla.
Bertrand S
,
Somorjai I
,
Garcia-Fernandez J
,
Lamonerie T
,
Escriva H
.
Abstract
BACKGROUND: 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.
RESULTS: 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.
CONCLUSION: 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.
Figure 1. Domain organization of the planarian nou-darake protein. Domain organization follows that proposed by the SMART online software. Positions at the beginning and end of each domain in the protein sequence are indicated. Ig: Immunoglobulin.
Figure 2. Phylogenetic analysis of the FGFRL1 putative orthologues. Phylogenetic tree estimated under the JTT+I+G model (RAxML with rapid bootstrap analysis with 100 bootstrapping runs). VEGFR sequences from vertebrates were used as the outgroup. FGFR sequences are indicated in blue and FGFRL1 sequences in red. The species abbreviations are as follows: BRABE: Branchiostoma belcheri, BRAFL: Branchiostoma floridae, BRUMA: Brugia malayi, CAEBR: Caenorhabditis briggsae, CAEEL: Caenorhabditis elegans, CAPSP: Capitella sp.I, CIOIN: Ciona intestinalis, CIOSA: Ciona savignyi, DANRE: Danio rerio, DAPPU: Daphnia pulex, DROME: Drosophila melanogaster, DUGJA: Dugesia japonica, GALGA: Gallus gallus, HOMSA: Homo sapiens, LOTGI: Lottia gigantea, MUSMU: Mus musculus, RATNO: Rattus norvegicus, STRPU: Strongylocentrotus purpuratus, TAKRU: Takifugu rubripes, TETNI: Tetraodon nigroviridis, XENLA: Xenopus laevis, XENTR: Xenopus tropicalis.
Figure 3. Schematic representation of the exon/intron organization of the FGFRL1 orthologous genes in different metazoan species. A schematic phylogenetic tree on the left indicates the evolutionary position of the different species studied. Boxes represent exons. Only exon size is proportional. Colour code is indicated in the figure. The colour of an exon means it contains the full (colour), or partial (hatched) corresponding domain. The exon/intron structures correspond to the data available in the jgi , Genbank , and ensembl databases.
Figure 4. Genomic position of the FGFRL1, FGF8/17/18 and FGFR orthologues in several metazoan species. Orthologous genes are schematized by boxes with the same colour. The position on the chromosomes or scaffolds is given according to the jgi , Genbank , and ensembl databases. Orthology for the Drosophila and nematode genes is given in parentheses. HTL: heartless, BTL: breathless, BNL: branchless, THS:thisbe, PYR: pyramus, EGL: EGg Laying defective.
Figure 5. Embryonic expression of amphioxus FGFRL1. Anterior is towards the left, and dorsal is up in the side views. Scale bars = 50 μm. (A) Side view of a gastrula stage embryo showing high expression of FGFRL1 in the anterior dorsal region. (B) Side view of an early neurula stage embryo. (C) Dorsal view of the embryo shown in (B). (D) Side view of a mid-neurula stage embryo with expression in the anterior region of the mesendoderm and neuroectdoderm as well as in the most anterior epidermis. (E) and (D) Dorsal views of the embryo shown in (D). (G) Side view of a late neurula stage embryo with labelling in the notochord, mainly in its most anterior part (white arrowhead), in the cerebral vesicle (black arrowhead) as well as in the anterior-most epidermis and in the pharyngeal endoderm. (H) Side view of a late neurula stage embryo showing expression in the cerebral vesicle (black arrowhead), in the notochord, mainly in its most anterior region (black arrow), and in the endoderm, with a high level in the region of the club-shaped gland anlagen (double black arrowhead). (I) Side view of the head of a larva. FGFRL1 is expressed in the cerebral vesicle around the frontal eye (black arrowhead), in the notochord with a high level in the most rostral region (black arrow), in the pre-oral pit (double black arrowhead), in the anterior region of the pharyngeal cavity (white arrow) and in the club-shaped gland (white arrowhead). (J) Side view of the tail of the specimen shown in (I) with labelling in the tailbud (black arrow) and in the anus (black arrowhead).
Figure 6. Embryonic expression of mouse FGFRL1. (A) E7.5 embryo showing FGFRL1 expression in the most anterior and posterior embryonic territories. (B) Side view of an E8.5 embryo. (C, D) Posterior view of the embryo shown in (B) with focus on the brain and the trunk respectively. At this stage expression is clearly observed in the somites, the tailbud and the anterior and posterior brain. (E) Side view of an E9.5 stage embryo showing expression of FGFRL1 in the frontonasal region, the otic vesicle, the somites, the forelimb buds and the tailbud. (F, G) Side views of an E10.5 stage embryo showing expression similar to E9.5 embryos. At this stage the hindlimb buds are developing and also express FGFRL1. (H, I) Side views of E11.5 embryos. Expression is detected in the frontal region of the brain, in the branchial arches, the otic vesicle, the tailbud and in the chondrogenic regions of the trunk and limbs.
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