Equipe ATIPE de l'UPRES-A 8080 Développement et Evolution, Orsay, France;
Laboratoire d'Ichtyologie et Service de Systématique moléculaire, Muséum National d'Histoire Naturelle, Paris, France
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Abstract |
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Introduction |
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The molecular basis for these functional diversifications has been addressed by experiments consisting of the replacement of either Otx1 or Otx2 coding regions by the paralogous form in knock-in mice. These experiments have shown that differential transcriptional controls could largely, but not exclusively, account for the differences observed between Otx1-/- and Otx2-/- mutant phenotypes. When expressed under Otx2 endogenous regulatory sequences, Otx1 can completely restore the gastrulation defects observed in Otx2-/- mice. However, at later stages, the specification of the prosencephalon and the mesencephalon remains defective (Acampora et al. 1998
; Suda et al. 1999
). On the other hand, Otx2 can compensate for most Otx1-/- defects in knock-in mice except for the deletion of the lateral semicircular canal in all animals studied, and with lower penetrance for several eye defects, including the absence of ciliary process (Morsli et al. 1999
; Acampora et al. 1999
).
A comparative analysis of vertebrate Otx genes in a wide range of species provides an alternative approach to address the molecular mechanisms underlying their functional diversification and possible links to gene duplication events. Most studies thus far have focused on osteichthyan species. Otx genes have been characterized in zebrafish (Li et al. 1994
; Mori et al. 1994
; Mercier et al. 1995
), two anurans, Xenopus laevis (Pannese et al. 1995
; Kablar et al. 1996
) and Eleutherodactylus coqui (Fang and Elinson 1999
), chick (Bally-Cuif et al. 1995
), and several mammals (Simeone et al. 1992; 1993
). In all of these species, genes clearly related to the mouse Otx1 and Otx2 paralogous forms have been unambiguously recognized, thus demonstrating the presence of two orthology classes among osteichthyans. Comparative analyses with amphioxus Otx have provided strong evidence that the corresponding duplication event took place prior to the splitting between actinopterygians and sarcopterygians but after the emergence of cephalochordates (Williams and Holland 1998
). In contrast, Crx genes, which are divergent members of the gene family, have been found only in mammals (mice, rats, humans, and oxen). Although these genes have aroused much interest in the past few years due to their involvement in human hereditary retinal degeneration, their origin is thus far completely unknown (Furukawa, Morrow, and Cepko 1997
; Chen et al. 1999
). In addition, other Otx genes have been isolated in Danio rerio (DrOtx3; Mori et al. 1994
; Mercier et al. 1995
) and, recently, in X. laevis (XlOtx5 and Otx5b; Kuroda et al. 2000
; Vignali et al. 2000
). No orthological relationships have been described between these genes and any of their vertebrate counterparts, and the chronology of the corresponding duplication events is unclear. Finally, three Otx genes have also been identified in Lampetra japonica (LjOtxA and LjOtxB; Ueki et al. 1998
) and Petromyzon marinus (PmOtx; Tomsa and Langeland 1999
). Their relationship with their osteichthyan counterparts remains to be clarified.
To further characterize orthological relationships among vertebrate Otx genes and gain new insights into the structural evolution of craniate Otx proteins, we have started a characterization of these genes in two species which belong to phylogenetic groups of early emergence among craniates, the hagfish Myxine glutinosa and a chondrichthyan, the dogfish Scyliorhinus canicula. The reedfish Erpetoichthys calabaricus, which belongs to the Cladistia, a group of basal emergence among actinopterygians, has also been included in this analysis. We report here partial sequences of three Otx genes in each of these species. Their comparison with other vertebrate sequences provides new insights into orthological relationships among gnathostome Otx genes and into the structural constraints acting on their protein products.
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Materials and Methods |
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Molecular Phylogenetic Analysis
Otx protein sequences were retrieved from the GenBank database. Their accession numbers are as follows: Branchiostoma floridae Otx, AF043740; P. marinus Otx, AF099746; L. japonica OtxA, AB012299; L. japonica OtxB, AB012300; D. rerio Otx1, D26172; D. rerio Otx2, D26173; D. rerio Otx3, D26174; X. laevis Otx2, U19813; X. laevis Otx2b, Z46972; X. laevis Otx5, AB034702; X. laevis Otx5b, AJ251846; Homo sapiens Otx1, P32242; H. sapiens Otx2, P32243; H. sapiens Crx, AF024711; Rattus norvegicus Otx1, L32602; R. norvegicus Crx, AB021129; Mus musculus Otx1, P80205; M. musculus Otx2, P80206; M. musculus Crx, U77615; Bos taurus Crx, AF154123. Two sequences were obtained from Kablar et al. (1996), X. laevis Otx1 and X. laevis Otx4. All these sequences were manually aligned using the ED program of the MUST package (Philippe 1993
). The nine new sequences determined in this study were added to this alignment of chordate Otx proteins, allowing for the comparison of 31 sequences.
In phylogenetic reconstructions, the Otx2 sequence from H. sapiens was excluded because of its identity to mouse Otx2 over the amplified segment. Phylogenetic trees were constructed using neighbor-joining (NJ) (Saitou and Nei 1987
), maximum-parsimony (MP), and maximum-likelihood (ML) algorithms using the MUST, version 2000, package (http://bos.snv.jussieu.fr/must2000.html); PAUP, version 3.1.1 (Swofford 1993
); and PROTML, version 2.3 (Adachi and Hasagawa 1996
), respectively. In the NJ analysis, distances were computed with the method of Kimura (1983)
. The MP tree was obtained by 100 random-addition heuristic search replicates and the tree bisection-reconnection (TBR) branch-swapping option. ML trees were constructed by the quick-add OTUs search with the JTT-f model of amino acid substitution, retaining the 2,000 top-ranking trees. Bootstrap proportions (BPs) were calculated by analysis of 1,000 replicates for NJ and MP and by the RELL method (Kishino, Miyata, and Hasegawa 1990
) on the 2,000 top-ranking trees for ML.
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Results |
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In each studied species, this PCR strategy led to the amplification of a heterogeneous population of fragments, approximately 550700 bp in length, which were subcloned and sequenced. Sequence comparisons of 24 subclones revealed the presence of three different fragments in the amplification products obtained from each of the three species under study, E. calabaricus, S. canicula, and M. glutinosa. These nine fragments unambiguously contain Otx coding sequences, as shown by their deduced amino acid sequences, which display a number of conserved motifs or residues previously identified in vertebrate Otx proteins. All share with their vertebrate counterparts a glutamine-rich stretch of variable length (Q15, positions 15 in the alignment; see Supplementary Material) immediately following the AKCRQQ motif, and the KXRX12KXK motif (positions 1623), which is also found in Amphi Otx. Except for one sequence of M. glutinosa (termed MgOtxD) which displays a divergent version (ILWNPA), they also contain the highly conserved (S/A)(I/L)WSPA motif (positions 111116). This motif has been identified in a wide range of metazoan Otx proteins, including those encoded by the flour beetle Tc-otd2 and the jellyfish Pc-Otx genes. Finally, sequences showing a similarity to the (D/E)CLDYK(D/E)(Q/P) motif (positions 365376), called the Otx tail and present immediately upstream of the C-terminal W(K/R)FQVL motif in all deuterostome Otx proteins, can be unambiguously identified at the expected position in each case. The nine Otx genes thus identified were termed EcOtx1, EcOtx2, and EcOtx5 in E. calabaricus; ScOtx1, ScOtx2, and ScOtx5 in S. canicula; and MgOtxA, MgOtxC, and MgOtxD in M. glutinosa, according to their orthology relationships with their vertebrate counterparts (described below).
Phylogenetic Analysis of Otx Genes in Craniates
The partial Otx protein sequences determined in E. calabaricus, S. canicula, and M. glutinosa were included in an exhaustive alignment containing their cephalochordate and vertebrate counterparts (see Supplementary Material). All of the craniate sequences could be confidently aligned over extended regions of similarity (bold characters in the alignment), which were used for phylogenetic analyses. Outside of these regions, more variable intervening segments were excluded from the analysis. From the alignment of 380 amino acids, 148 positions were kept, among which 101 corresponded to informative sites for parsimony. Phylogenetic reconstructions were carried out using the NJ, MP, and ML methods (fig. 1
). A single most-parsimonious tree (length = 479; retention index [RI] = 0.595; consistency index [CI] = 0.698) was obtained, and the length (L) of the ML tree was ln L = -2,615.9. Although the analyses were conducted unrooted, the resulting trees are shown rooted on MgOtxC and MgOtxD for convenience of presentation (fig. 1
). All three analyses confirm the presence of the Otx1 and Otx2 orthology classes already characterized in osteichthyans. In addition to the Otx1- and Otx2-related genes identified in zebrafish, Xenopus, and mammals, each of these classes contains one of the genes newly characterized in E. calabaricus (EcOtx1 and EcOtx2) and S. canicula (ScOtx1 and ScOtx2). These two classes are always found to be monophyletic whatever the reconstruction method used. However, the clustering of the gnathostome Otx2 sequences is more highly supported (with BP values ranging from 75% to 97%) than the clustering of the Otx1-related paralogous genes (with BP reaching a maximum of 67% for NJ). Inside the Otx2 class, the classical phylogeny of gnathostomes is recovered by the three reconstruction methods, except for the position of actinopterygians, which form a paraphyletic group in the MP tree (BP < 50%). In particular, the early emergence of S. canicula is always supported by high bootstrap values (93%, 61%, and 97% in NJ, MP, and ML analyses, respectively). The splitting of actinopterygians and sarcopterygians into two well-defined groups also receives strong support in NJ and ML analyses (BP = 62% and 79% for actinopterygians, 77% and 84% for sarcopterygians). Inside the Otx1 class, the branching orders differ substantially depending on the reconstruction method used. If the monophyly of mammals, as well as the close relationship of Otx1 and Otx4 sequences in X. laevis, are always recovered and supported by high bootstrap values, the relative position of the two actinopterygians (E. calabaricus and D. rerio) and the chondrichthyan (S. canicula) is not resolved.
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As for the third gene identified in zebrafish (DrOtx3), it appears unrelated to the Otx1, Otx2, or Otx5/Crx classes in our tree reconstructions, always emerging before their separation. This result is incongruent with previously published studies which showed a clustering of DrOtx3 and DrOtx1 (Williams and Holland 1998
). However, the early emergence observed in our analyses for DrOtx3 is poorly supported. Furthermore, when only gnathostome sequences were included in the phylogenetic analyses, the zebrafish DrOtx1 and DrOtx3 sequences clustered together (data not shown). Together with the site-by-site analysis of the alignment in the more variable regions (see below), these results suggest that DrOtx3 may be a divergent member of the Otx1 class.
The lamprey and hagfish Otx sequences cannot be confidently assigned to any of the three classes identified in gnathostomes. Their relative branching orders appear variable depending on the reconstruction method used and most of the time are poorly resolved. A major exception lies in the clustering of LjOtxA with one of the hagfish genes (thereafter termed MgOtxA), which is observed in NJ, MP, and ML analyses. A close relationship between these two sequences is supported by high bootstrap values (96%, 95%, and 99% in NJ, ML, and MP analyses, respectively). In addition, a clustering of MgOtxD and PmOtx was obtained in the three phylogenetic reconstructions with bootstrap values above 50%. However, because of the high degree of divergence of these two sequences, we cannot exclude that this result may be due to a long-branch attraction artifact.
Phylogenetic Analysis of Amphioxus and Craniate Otx Sequences
In an attempt to root the craniate Otx phylogenetic tree, amphioxus Otx sequence was added for a new phylogenetic analysis (fig. 2 ). The portions of the alignment which were taken into account were the same as those previously used. Among the 150 sites used in this analysis, 136 corresponded to variable sites and 102 were informative for parsimony. As in the previous analysis, phylogenetic reconstructions were carried out using the NJ, MP, and ML methods. Ten equiparsimonius trees were found (length = 517; RI = 0.684; CI = 0.594), and the length of the ML tree was ln L = -2,790.86.
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The close relationship observed between LjOtxA and MgOtxA in the previous analysis was recovered with high bootstrap values in all three reconstruction methods. No clear conclusion could be reached concerning the relative order of emergence of the three gnathostome orthology classes, the cyclostome OtxA class, and the other lamprey and hagfish genes (PmOtx, LjOtxB, MgOtxC, and MgOtxD). It appeared variable depending on the reconstruction method used (data not shown), and none of the groupings appeared to be supported by significant bootstrap values (fig. 2 ).
Structural Evolution of the Otx1, Otx2, and Otx5/Crx Orthology Classes in Gnathostomes
To independently assess the existence of the three orthology classes identified in the phylogenetic analysis and gain deeper insight into their structural evolution, we performed a systematic search of motifs or residues specifically maintained in each of them. This analysis was carried out for the portions of the alignment which were included in the phylogenetic analysis and extended to the more variable intervening regions (see alignment). In the latter, no strongly supported alignment can be proposed between all gnathostome Otx proteins, but significant similarities can be identified within each of the four classes, respectively, containing Otx1/Otx4, Otx2/Otx2b, Otx5/Otx5b, and Crx sequences. In particular, the highly variable regions (positions 59105 and 121193) located immediately upstream and downstream of the WSP motif show an extensive divergence between Otx1, Otx2, Otx5, and Crx proteins but can be unambiguously aligned within each of these four classes. These close relationships strongly support the assignment of Sc/EcOtx1, Sc/EcOtx2, and Sc/EcOtx5 to the Otx1, Otx2, and Otx5 orthology classes, respectively. Most of the repetitive stretches of serine and histidine (positions 6275, 257263, 290299, and 307317), previously identified as hallmarks of osteichthyan Otx1-related genes, are also conserved in EcOtx1 and ScOtx1 but absent from all other craniate sequences, suggesting that they correspond to synapomorphies of the Otx1 orthology class. The only exception is the histidine stretch located at positions 290299, which appears to be restricted to a single additional H in ScOtx1. From position 257 to position 299, ScOtx1 sequence also provides new clues for understanding the structural evolution of Otx1-related genes, since it displays a 7-amino-acid motif (positions 270276) which has been deleted in all osteichthyan Otx1 proteins but is present in all other craniate sequences. While the relationship between osteichthyan Otx1 sequences and other vertebrate sequences remained unclear over this domain, the identification of this ancestral characteristic makes it possible to confidently align them with their craniate counterparts.
In gnathostomes, the characterization of Otx1-, Otx2-, and Otx5-related coding sequences in a wide range of species, including in all cases a chondrichthyan, at least one actinopterygian, and one osteichthyan, makes it possible to identify residues which have been selectively conserved within each of these three classes. A total of 15, 10, and 14 such amino acids, respectively, selectively maintained among Otx1, Otx2, and Otx5 protein sequences, could be identified. These residues are shaded in the alignment (Supplementary Material). They are present not only in the most variable regions of the proteins, which were excluded from the phylogenetic analysis, but also within the protein domains which can be unambiguously aligned between paralogous forms.
Using these distinctive features as a criterion, we studied the assignment of the zebrafish Otx3 and the mammalian Crx genes to the Otx1, Otx2, and Otx5 classes identified in gnathostomes. Over the protein domain studied, DrOtx3 displays 10/15 (positions 41, 43, 61, 62, 123, 219, 257, 262, 263, and 308) and 1/10 residues (position 284) specific for Otx1- and Otx2-related genes, respectively, but no residue specific for the Otx5 class. This suggests that it may be a divergent member of the Otx1 orthology class. In line with this conclusion, it exhibits the serine and histidine stretches which are also characteristic for this class (positions 6274, 257266, 290294, and 307313). As for the four mammalian Crx genes, their deduced amino acid sequences share 9 selectively conserved residues out of 14 with Otx5 sequences but appear unrelated to Otx1 or Otx2 forms over the residues specific for these classes. This result thus supports their orthological relationship with Otx5 genes, as already pointed out by the phylogenetic analysis.
The Otx sequences characterized in lamprey and in hagfish show no clear relationship with either the gnathostome Otx1, Otx2, or Otx5 form over the residues specific for each class. In contrast, L. japonica and M. glutinosa OtxA proteins share a total of eight residues which are not found in any other craniate Otx form. While the ancestral state cannot be determined in most cases, the G (position 358) which corresponds in both LjOtxA and MgOtxA to the N shared by the cephalochordate and all other craniate Otx sequences (except Crx forms, which display a T) is likely to correspond to a derived character.
Otx Tail Duplication in Craniate Otx Proteins
Phylogenetic reconstructions taking the whole protein sequence into account have provided strong evidence that the duplication events which have given rise to the lamprey Otx genes and the gnathostome Otx1 and Otx2 orthology classes took place after the splitting between the cephalochordate and vertebrate lineages. In line with this conclusion, it has been shown that these genes share sequence features which are not observed in echinoderms, ascidians, or cephalochordates. In particular, all of them display an imperfect tandem duplication of an 1825-amino-acid motif containing the Otx tail (domains A and B in the alignment; see Supplementary Material). In contrast, a single copy is present in echinoderms, ascidians, and amphioxi (Williams and Holland 1998
).
Like their orthologs in sarcopterygians and in zebrafish, the Otx1 and Otx2 coding sequences identified in E. calabaricus and in S. canicula contain two copies of the C-terminal domain. To address the chronology of the duplication events that have generated the Otx5/Crx orthology class identified in gnathostomes and the multigene family characterized in hagfish, we examined each of the sequences reported in this study for the presence of this C-terminal repeat. Both domains A and B are unambiguously present at the C-terminal ends of the four Otx5 proteins identified in X. laevis, E. calabaricus, and S. canicula (positions 329356 and 357380). However, the presence of this tandem duplication has not been recognized in the amino acid sequence encoded by mammalian Crx genes (Furukawa, Morrow, and Cepko 1997
). Since they cluster with Otx5 genes in our phylogenetic reconstructions, we searched for the presence of a duplicated C-terminal domain in Crx sequences. Despite a 4-amino-acid deletion in the N-terminal part of domain A, all four mammalian Crx sequences contain the DSLEFKDPTGTWK motif, which can be unambiguously aligned with the C-terminal part of this domain (positions 337356). Immediately downstream (positions 357380), domain B can also be unambiguously recognized, although its N-terminal consensus in Otx1, Otx2, and Otx5 sequences (LNF, positions 357359) is replaced by the motif FTY in Crx proteins. Although degenerate, the C-terminal repeat is thus present in Crx amino acid sequences. In hagfish, the three sequences identified also contain both domains A and B at their C-terminal ends (positions 329356 and 357380), with several single-amino-acid insertions or deletions.
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Discussion |
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Gene Duplications in the Otx Gene Family
The basal emergence of the chondrichthyans has recently been challenged on the basis of mitochondrial DNA analyses (Rasmussen and Arnason 1999
). However, both the phylogenies obtained for Otx2 and Otx5 genes and the site-by-site analysis of gnathostome Otx1 sequences strongly support the basal position of the chondrichthyans as a sister group of osteichthyans. In this phylogeny, the identification of S. canicula Otx genes belonging to the three orthology classes characterized in osteichthyans indicates that the corresponding duplication events took place prior to the splitting between chondrichthyans and osteichthyans, more than 420 MYA (Benton 1990
). The tandem repeat of the C-terminal motif observed in Otx1- and Otx2-related proteins, as well as in the three Otx proteins identified in L. japonica and P. marinus, has provided a strong argument that the corresponding genes all derive from duplications of a single ancestral gene which occurred after the splitting of cephalochordates (Ueki et al. 1998
; Williams and Holland 1998
; Tomsa and Langeland 1999
). This conclusion can now be extended to the gnathostome Otx5/Crx genes and the three copies identified in hagfish, suggesting that the presence of this C-terminal repeat is a synapomorphy of all craniate Otx proteins. In contrast, the chronology of the duplication events that gave rise to the three orthology classes characterized in gnathostomes relative to the emergence of lampreys and hagfishes could not be resolved in our analyses. Independent duplication events provide the simplest hypothesis to account for the absence of sequence relationships between the lamprey or hagfish genes and the gnathostome Otx1, Otx2, and Otx5/Crx orthology classes. However, the possibility that gene duplications occurred prior to the splitting of lampreys and hagfishes cannot be formally ruled out. A relatively short time interval between such genetic events and the speciation events which generated these lineages could actually make orthological relationships with the gnathostome Otx genes difficult to detect.
These results are very similar to those obtained in a number of other genetic systems in two respects. First, they show the presence of unambiguous orthology classes in all jawed vertebrates, including chondrichthyans. Similar conclusions have been reached in a number of other molecular studies also including chondrichthyan sequences (Sidow 1992
; Duguay et al. 1995
; Kandil et al. 1996
; Li, Keith, and Evans 1996
; Hahn et al. 1997
; Flajnik et al. 1999
). Second, in hagfish, as in lamprey, they provide an additional example of a multigene family resulting from duplications of a single ancestral copy in the craniate lineage. An absence of clear orthological relationships between the paralogous genes identified in these species and their gnathostome counterparts has also been a recurrent conclusion for the different studied systems (Sidow 1992
; Li, Keith, and Evans 1996
; Sharman and Holland 1998
; Kuraku et al. 1999
; Suga et al. 1999
). Taken together, these results support the hypothesis that the duplication of Otx genes may have been part of massive amplification events which took place after the emergence of cephalochordates and prior to the splitting between chondrichthyans and osteichthyans (Williams and Holland 1998
). However, a more precise chronology of such genetic events remains elusive.
Functional Evolution of Gnathostome Otx Genes
Several lines of evidence indicate that for some of the complex functions fulfilled by Otx genes in gnathostomes, paralogous Otx proteins may share largely equivalent biochemical properties. For instance, all the gastrulation defects observed in Otx2-/- mouse embryos, including the initial induction of anterior neuroectoderm, can be compensated when the mouse Otx2 coding region is replaced by its Otx1 counterpart in knock-in experiments (Acampora et al. 1998
; Suda et al. 1999
). Likewise, the replacement of Otx1 by Otx2 restores most of the brain and sense organ abnormalities observed in Otx1-/- mice (Acampora et al. 1999
). In Xenopus, the phenotypes induced by overexpressions of XlOtx2 and XlOtx5/Otx5b are also very similar, suggesting that both paralogs are involved in the early specification of anterior regions (Andreazzoli, Pannese, and Boncinelli 1997
; Kuroda et al. 2000
; Vignali et al. 2000
). On the other hand, the identification of amino acid differences between Otx1, Otx2, and Otx5 proteins, which appear to be selectively maintained among a wide range of gnathostomes, provides strong evidence that different structural constraints act on each orthology class. Whatever the precise chronology of Otx genes duplication events in craniates, these structural constraints were fixed after the cyclostome/gnathostome splitting but prior to their radiation. This suggests that functions which are unique to each orthology class were also fixed in the gnathostome lineage, prior to the chondrichthyan/osteichthyan splitting. Results of knock-in experiments and comparisons of the expression patterns of gnathostome Otx genes are consistent with this hypothesis. The role played by mouse Otx1 in the lateral semicircular canal formation could provide an example of such specializations, since it cannot be compensated for by the paralogous form Otx2 in knock-in experiments. Concerning Otx2, it is not currently known whether the jaw defects observed in Otx2+/- mutant mice (Matsuo et al. 1995
) can be compensated by paralogous genes. In contrast, the replacement of Otx2 coding sequence by the paralogous Otx1 form in mice results in a defective prosencephalon specification during neurulation, raising the possibility that this role may be specific to the Otx2 orthology class. As for the Otx5/Crx orthology class, it may have been recruited for specific roles in photoreceptor development, as suggested by the specific transcription pattern shared by amphibian Otx5 genes in the developing eye and epiphysis and the analysis of Crx-/- mice. The analysis of ScOtx5 expression should help to test this hypothesis.
Taken together, these results suggest that while some roles of Otx genes may be fulfilled by different combinations of paralogous genes depending on the species considered, each gnathostome orthology class has also been recruited for specific functions. Residues corresponding to selectively maintained differences between the three orthology classes may be important in determining the specificity of the molecular interactions which control these processes. The identification of such interactions, together with detailed analyses of the structure/function relationships of gnathostome Otx genes, will be required to elucidate the genetic and molecular mechanisms underlying their functional diversification.
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Supplementary Material |
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Acknowledgements |
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Footnotes |
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1 Present address: Glycobiologie et Biotechnologie EA 1074, Faculté des Sciences, Université de Limoges, Limoges, France.
2 Present address: Génétique du Développement et Evolution, Institut Jacques Monod, Paris, France.
1 Keywords: Otx
craniate phylogeny
gene duplication
dogfish
reedfish
hagfish
2 Address for correspondence and reprints: Sylvie Mazan, Equipe ATIPE de l'UPRES-A 8080, Bât. 441, Université Paris-Sud, 91405 Orsay Cedex, France. sylvie.mazan{at}ibaic.u-psud.fr
.
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References |
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